Tony Wyss-Coray, PhD

All Publications

• Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer's disease. Nature genetics Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Phillips, B., Wang, Y., Liu, M., Ali, M., Beric, A., Gorijala, P., Kohlfeld, P., Budde, J., Levey, A. I., Morris, J. C., Perrin, R. J., Ruiz, A., Marquié, M., Boada, M., de Rojas, I., Rutledge, J., Oh, H., Wilson, E. N., Le Guen, Y., Reus, L. M., Tijms, B., Visser, P. J., van der Lee, S. J., Pijnenburg, Y. A., Teunissen, C. E., Del Campo Milan, M., Alvarez, I., Aguilar, M., Greicius, M. D., Pastor, P., Pulford, D. J., Ibanez, L., Wyss-Coray, T., Sung, Y. J., Cruchaga, C. 2024

  Abstract

  The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

  View details for DOI 10.1038/s41588-024-01972-8

  View details for PubMedID 39528825

  View details for PubMedCentralID 9605867

• Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity. Aging Lyu, Y. X., Fu, Q., Wilczok, D., Ying, K., King, A., Antebi, A., Vojta, A., Stolzing, A., Moskalev, A., Georgievskaya, A., Maier, A. B., Olsen, A., Groth, A., Simon, A. K., Brunet, A., Jamil, A., Kulaga, A., Bhatti, A., Yaden, B., Pedersen, B. K., Schumacher, B., Djordjevic, B., Kennedy, B., Chen, C., Huang, C. Y., Correll, C. U., Murphy, C. T., Ewald, C. Y., Chen, D., Valenzano, D. R., Sołdacki, D., Erritzoe, D., Meyer, D., Sinclair, D. A., Chini, E. N., Teeling, E. C., Morgen, E., Verdin, E., Vernet, E., Pinilla, E., Fang, E. F., Bischof, E., Mercken, E. M., Finger, F., Kuipers, F., Pun, F. W., Gyülveszi, G., Civiletto, G., Zmudze, G., Blander, G., Pincus, H. A., McClure, J., Kirkland, J. L., Peyer, J., Justice, J. N., Vijg, J., Gruhn, J. R., McLaughlin, J., Mannick, J., Passos, J., Baur, J. A., Betts-LaCroix, J., Sedivy, J. M., Speakman, J. R., Shlain, J., von Maltzahn, J., Andreasson, K. I., Moody, K., Palikaras, K., Fortney, K., Niedernhofer, L. J., Rasmussen, L. J., Veenhoff, L. M., Melton, L., Ferrucci, L., Quarta, M., Koval, M., Marinova, M., Hamalainen, M., Unfried, M., Ringel, M. S., Filipovic, M., Topors, M., Mitin, N., Roy, N., Pintar, N., Barzilai, N., Binetti, P., Singh, P., Kohlhaas, P., Robbins, P. D., Rubin, P., Fedichev, P. O., Kamya, P., Muñoz-Canoves, P., de Cabo, R., Faragher, R. G., Konrad, R., Ripa, R., Mansukhani, R., Büttner, S., Wickström, S. A., Brunemeier, S., Jakimov, S., Luo, S., Rosenzweig-Lipson, S., Tsai, S. Y., Dimmeler, S., Rando, T. A., Peterson, T. R., Woods, T., Wyss-Coray, T., Finkel, T., Strauss, T., Gladyshev, V. N., Longo, V. D., Dwaraka, V. B., Gorbunova, V., Acosta-Rodríguez, V. A., Sorrentino, V., Sebastiano, V., Li, W., Suh, Y., Zhavoronkov, A., Scheibye-Knudsen, M., Bakula, D. 2024; 16

  Abstract

  The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

  View details for DOI 10.18632/aging.206135

  View details for PubMedID 39418098

• Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. Research square Wilson, E., Umans, J., Swarovski, M., Minhas, P., Midttun, Ø., Ulvik, A. A., Shahid-Besanti, M., Linortner, P., Mhatre, S., Wang, Q., Channappa, D., Corso, N., Tian, L., Fredericks, C., Kerchner, G., Plowey, E., Cholerton, B., Ueland, P., Zabetian, C., Gray, N., Quinn, J., Montine, T., Sha, S., Longo, F., Wolk, D., Chen-Plotkin, A., Henderson, V., Wyss-Coray, T., Wagner, A., Mormino, E., Aghaeepour, N., Poston, K., Andreasson, K. 2024

  Abstract

  Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

  View details for DOI 10.21203/rs.3.rs-4980210/v1

  View details for PubMedID 39399688

  View details for PubMedCentralID PMC11469709

• CSF proteomics identifies early changes in autosomal dominant Alzheimer's disease. Cell Shen, Y., Timsina, J., Heo, G., Beric, A., Ali, M., Wang, C., Yang, C., Wang, Y., Western, D., Liu, M., Gorijala, P., Budde, J., Do, A., Liu, H., Gordon, B., Llibre-Guerra, J. J., Joseph-Mathurin, N., Perrin, R. J., Maschi, D., Wyss-Coray, T., Pastor, P., Renton, A. E., Surace, E. I., Johnson, E. C., Levey, A. I., Alvarez, I., Levin, J., Ringman, J. M., Allegri, R. F., Seyfried, N., Day, G. S., Wu, Q., Fernández, M. V., Tarawneh, R., McDade, E., Morris, J. C., Bateman, R. J., Goate, A., Ibanez, L., Sung, Y. J., Cruchaga, C. 2024

  Abstract

  In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers.

  View details for DOI 10.1016/j.cell.2024.08.049

  View details for PubMedID 39332414

• Plasma and CSF biomarkers of aging and cognitive decline in Caribbean vervets. Alzheimer's & dementia : the journal of the Alzheimer's Association Varma, C., Luo, E., Bostrom, G., Bathini, P., Berdnik, D., Wyss-Coray, T., Zhao, T., Dong, X., Ervin, F. R., Beierschmitt, A., Palmour, R. M., Lemere, C. A. 2024

  Abstract

  Vervets are non-human primates that share high genetic homology with humans and develop amyloid beta (Aβ) pathology with aging. We expand current knowledge by examining Aβ pathology, aging, cognition, and biomarker proteomics.Amyloid immunoreactivity in the frontal cortex and temporal cortex/hippocampal regions from archived vervet brain samples ranging from young adulthood to old age was quantified. We also obtained cognitive scores, plasma samples, and cerebrospinal fluid (CSF) samples in additional animals. Plasma and CSF proteins were quantified with platforms utilizing human antibodies.We found age-related increases in Aβ deposition in both brain regions. Bioinformatic analyses assessed associations between biomarkers and age, sex, cognition, and CSF Aβ levels, revealing changes in proteins related to immune-related inflammation, metabolism, and cellular processes.Vervets are an effective model of aging and early-stage Alzheimer's disease, and we provide translational biomarker data that both align with previous results in humans and provide a basis for future investigations.We found changes in immune and metabolic plasma biomarkers associated with age and cognition. Cerebrospinal fluid (CSF) biomarkers revealed changes in cell signaling indicative of adaptative processes. TNFRSF19 (TROY) and Artemin co-localize with Alzheimer's disease pathology. Vervets are a relevant model for translational studies of early-stage Alzheimer's disease.

  View details for DOI 10.1002/alz.14038

  View details for PubMedID 38946666

• Plasma proteomics in the UK Biobank reveals youthful brains and immune systems promote healthspan and longevity. bioRxiv : the preprint server for biology Oh, H. S., Le Guen, Y., Rappoport, N., Urey, D. Y., Rutledge, J., Brunet, A., Greicius, M. D., Wyss-Coray, T. 2024

  Abstract

  Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements. Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.

  View details for DOI 10.1101/2024.06.07.597771

  View details for PubMedID 38915561

  View details for PubMedCentralID PMC11195058

• Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes. Research square Chou, C. C., Vest, R., Prado, M. A., Wilson-Grady, J., Paulo, J. A., Shibuya, Y., Moran-Losada, P., Lee, T. T., Luo, J., Gygi, S. P., Kelly, J. W., Finley, D., Wernig, M., Wyss-Coray, T., Frydman, J. 2024

  Abstract

  Aging is a prominent risk factor for Alzheimer's disease (AD), but the cellular mechanisms underlying neuronal phenotypes remain elusive. Both accumulation of amyloid plaques and neurofibrillary tangles in the brain1 and age-linked organelle deficits2-7 are proposed as causes of AD phenotypes but the relationship between these events is unclear. Here, we address this question using a transdifferentiated neuron (tNeuron) model directly from human dermal fibroblasts. Patient-derived tNeurons retain aging hallmarks and exhibit AD-linked deficits. Quantitative tNeuron proteomic analyses identify aging and AD-linked deficits in proteostasis and organelle homeostasis, particularly affecting endosome-lysosomal components. The proteostasis and lysosomal homeostasis deficits in aged tNeurons are exacerbated in sporadic and familial AD tNeurons, promoting constitutive lysosomal damage and defects in ESCRT-mediated repair. We find deficits in neuronal lysosomal homeostasis lead to inflammatory cytokine secretion, cell death and spontaneous development of Aß and phospho-Tau deposits. These proteotoxic inclusions co-localize with lysosomes and damage markers and resemble inclusions in brain tissue from AD patients and APP-transgenic mice. Supporting the centrality of lysosomal deficits driving AD phenotypes, lysosome-function enhancing compounds reduce AD-associated cytokine secretion and Aβ deposits. We conclude that proteostasis and organelle deficits are upstream initiating factors leading to neuronal aging and AD phenotypes.

  View details for DOI 10.21203/rs.3.rs-4407236/v1

  View details for PubMedID 38853828

  View details for PubMedCentralID PMC11160905

• A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model. Alzheimer's & dementia : the journal of the Alzheimer's Association Latif-Hernandez, A., Yang, T., Raymond-Butler, R. 3., Losada, P. M., Minhas, P. S., White, H., Tran, K. C., Liu, H., Simmons, D. A., Langness, V., Andreasson, K. I., Wyss-Coray, T., Longo, F. M. 2024

  Abstract

  INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Abeta) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction.METHODS: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls. Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing.RESULTS: In APPL/S mice, BD10-2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium-calmodulin-dependent kinase II (CaMKII), and AMPA-type glutamate receptors containing the subunit GluA1; enhanced activity-dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription.DISCUSSION: BD10-2 prevented APPL/S/Abeta-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.HIGHLIGHTS: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long-term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity-dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD-relevant human-mouse co-expression modules.

  View details for DOI 10.1002/alz.13857

  View details for PubMedID 38779814

• Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis. Nature neuroscience Mader, M. M., Napole, A., Wu, D., Atkins, M., Scavetti, A., Shibuya, Y., Foltz, A., Hahn, O., Yoo, Y., Danziger, R., Tan, C., Wyss-Coray, T., Steinman, L., Wernig, M. 2024

  Abstract

  Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing-remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector Tcells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

  View details for DOI 10.1038/s41593-024-01609-3

  View details for PubMedID 38514857

• SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination. Proceedings of the National Academy of Sciences of the United States of America Iram, T., Garcia, M. A., Amand, J., Kaur, A., Atkins, M., Iyer, M., Lam, M., Ambiel, N., Jorgens, D. M., Keller, A., Wyss-Coray, T., Kern, F., Zuchero, J. B. 2024; 121 (12): e2307250121

  Abstract

  Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the mechanistic role of SRF in oligodendrocyte lineage cells. Here, we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in oligodendrocyte precursor cells and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Surprisingly, oligodendrocyte-restricted loss of SRF results in upregulation of gene signatures associated with aging and neurodegenerative diseases. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies an essential pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease.

  View details for DOI 10.1073/pnas.2307250121

  View details for PubMedID 38483990

• CSF proteomic profiling with amyloid/tau positivity identifies distinctive sex-different alteration of multiple proteins involved in Alzheimer's disease. medRxiv : the preprint server for health sciences Do, A. N., Ali, M., Timsina, J., Wang, L., Western, D., Liu, M., Sanford, J., Rosende-Roca, M., Boada, M., Puerta, R., Wilson, T., Ruiz, A., Pastor, P., Wyss-Coray, T., Cruchaga, C., Sung, Y. J. 2024

  Abstract

  In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific proteins strongly predicted amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152 proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone (used for pain), daunorubicin, and verteporfin for treating AD males. In contrast, female-specific proteins, enriched in neurons, were involved in phosphoserine residue binding including cytokine activities. The female network exhibits strong connections among 51 proteins and highlighted JUN and 14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested biperiden (for muscle control of Parkinson's disease), nimodipine (for cerebral vasospasm), quinostatin and ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions.

  View details for DOI 10.1101/2024.03.15.24304164

  View details for PubMedID 38559166

  View details for PubMedCentralID PMC10980123

• APOE4/4 is linked to damaging lipid droplets in Alzheimer's diseasemicroglia. Nature Haney, M. S., Palovics, R., Munson, C. N., Long, C., Johansson, P. K., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., Wyss-Coray, T. 2024

  Abstract

  Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Abeta induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

  View details for DOI 10.1038/s41586-024-07185-7

  View details for PubMedID 38480892

• Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease. Acta neuropathologica Rutledge, J., Lehallier, B., Zarifkar, P., Losada, P. M., Shahid-Besanti, M., Western, D., Gorijala, P., Ryman, S., Yutsis, M., Deutsch, G. K., Mormino, E., Trelle, A., Wagner, A. D., Kerchner, G. A., Tian, L., Cruchaga, C., Henderson, V. W., Montine, T. J., Borghammer, P., Wyss-Coray, T., Poston, K. L. 2024; 147 (1): 52

  Abstract

  Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

  View details for DOI 10.1007/s00401-024-02706-0

  View details for PubMedID 38467937

  View details for PubMedCentralID 3995906

• An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome. Nature communications Liu, S., Ezran, C., Wang, M. F., Li, Z., Awayan, K., Long, J. Z., De Vlaminck, I., Wang, S., Epelbaum, J., Kuo, C. S., Terrien, J., Krasnow, M. A., Ferrell, J. E. 2024; 15 (1): 2188

  Abstract

  Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

  View details for DOI 10.1038/s41467-024-46070-9

  View details for PubMedID 38467625

  View details for PubMedCentralID 1540572

• Multi-cohort cerebrospinal fluid proteomics identifies robust molecular signatures for asymptomatic and symptomatic Alzheimer's disease. Research square Cruchaga, C., Ali, M., Shen, Y., Do, A., Wang, L., Western, D., Liu, M., Beric, A., Budde, J., Gentsch, J., Schindler, S., Morris, J., Holtzman, D., Fernandez, M., Ruiz, A., Alvarez, I., Aguilar, M., Pastor, P., Rutledge, J., Oh, H., Wilson, E., Le Guen, Y., Khalid, R., Robins, C., Pulford, D., Ibanez, L., Wyss-Coray, T., Ju Sung, Y. 2024

  Abstract

  Changes in Amyloid-beta (A), hyperphosphorylated Tau (T) in brain and cerebrospinal fluid (CSF) precedes AD symptoms, making CSF proteome a potential avenue to understand the pathophysiology and facilitate reliable diagnostics and therapies. Using the AT framework and a three-stage study design (discovery, replication, and meta-analysis), we identified 2,173 proteins dysregulated in AD, that were further validated in a third totally independent cohort. Machine learning was implemented to create and validate highly accurate and replicable (AUC>0.90) models that predict AD biomarker positivity and clinical status. These models can also identify people that will convert to AD and those AD cases with faster progression. The associated proteins cluster in four different protein pseudo-trajectories groups spanning the AD continuum and were enrichment in specific pathways including neuronal death, apoptosis and tau phosphorylation (early stages), microglia dysregulation and endolysosomal dysfuncton(mid-stages), brain plasticity and longevity (mid-stages) and late microglia-neuron crosstalk (late stages).

  View details for DOI 10.21203/rs.3.rs-3631708/v1

  View details for PubMedID 38410465

• Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease. Molecular neurodegeneration Wang, L., Nykänen, N. P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., Brock, W., Marquié, M., Boada, M., Alvarez, I., Aguilar, M., Pastor, P., Ruiz, A., Puerta, R., Orellana, A., Rutledge, J., Oh, H., Greicius, M. D., Le Guen, Y., Perrin, R. J., Wyss-Coray, T., Jefferson, A., Hohman, T. J., Graff-Radford, N., Mori, H., Goate, A., Levin, J., Sung, Y. J., Cruchaga, C. 2024; 19 (1): 1

  Abstract

  Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

  View details for DOI 10.1186/s13024-023-00687-4

  View details for PubMedID 38172904

  View details for PubMedCentralID PMC10763080

• Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes. Alzheimer's & dementia : the journal of the Alzheimer's Association Abiose, O., Rutledge, J., Moran-Losada, P., Belloy, M. E., Wilson, E. N., He, Z., Trelle, A. N., Channappa, D., Romero, A., Park, J., Yutsis, M. V., Sha, S. J., Andreasson, K. I., Poston, K. L., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Mormino, E. C. 2023

  Abstract

  In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults.We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes.We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = -2.00, p = 0.005, M7: β = -2.39, p < 0.001).In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

  View details for DOI 10.1002/alz.13576

  View details for PubMedID 38146099

• Organ aging signatures in the plasma proteome track health and disease. Nature Oh, H. S., Rutledge, J., Nachun, D., Pálovics, R., Abiose, O., Moran-Losada, P., Channappa, D., Urey, D. Y., Kim, K., Sung, Y. J., Wang, L., Timsina, J., Western, D., Liu, M., Kohlfeld, P., Budde, J., Wilson, E. N., Guen, Y., Maurer, T. M., Haney, M., Yang, A. C., He, Z., Greicius, M. D., Andreasson, K. I., Sathyan, S., Weiss, E. F., Milman, S., Barzilai, N., Cruchaga, C., Wagner, A. D., Mormino, E., Lehallier, B., Henderson, V. W., Longo, F. M., Montgomery, S. B., Wyss-Coray, T. 2023; 624 (7990): 164-172

  Abstract

  Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

  View details for DOI 10.1038/s41586-023-06802-1

  View details for PubMedID 38057571

  View details for PubMedCentralID PMC10700136

• ZEBRA: a hierarchically integrated gene expression atlas of the murine and human brain at single-cell resolution. Nucleic acids research Flotho, M., Amand, J., Hirsch, P., Grandke, F., Wyss-Coray, T., Keller, A., Kern, F. 2023

  Abstract

  The molecular causes and mechanisms of neurodegenerative diseases remain poorly understood. A growing number of single-cell studies have implicated various neural, glial, and immune cell subtypes to affect the mammalian central nervous system in many age-related disorders. Integrating this body of transcriptomic evidence into a comprehensive and reproducible framework poses several computational challenges. Here, we introduce ZEBRA, a large single-cell and single-nucleus RNA-seq database. ZEBRA integrates and normalizes gene expression and metadata from 33 studies, encompassing 4.2 million human and mouse brain cells sampled from 39 brain regions. It incorporates samples from patients with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and Multiple sclerosis, as well as samples from relevant mouse models. We employed scVI, a deep probabilistic auto-encoder model, to integrate the samples and curated both cell and sample metadata for downstream analysis. ZEBRA allows for cell-type and disease-specific markers to be explored and compared between sample conditions and brain regions, a cell composition analysis, and gene-wise feature mappings. Our comprehensive molecular database facilitates the generation of data-driven hypotheses, enhancing our understanding of mammalian brain function during aging and disease. The data sets, along with an interactive database are freely available at https://www.ccb.uni-saarland.de/zebra.

  View details for DOI 10.1093/nar/gkad990

  View details for PubMedID 37941147

• Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis. Cell reports. Medicine Tsitsou-Kampeli, A., Suzzi, S., Kenigsbuch, M., Satomi, A., Strobelt, R., Singer, O., Feldmesser, E., Purnapatre, M., Colaiuta, S. P., David, E., Cahalon, L., Hahn, O., Wyss-Coray, T., Shaul, Y., Amit, I., Schwartz, M. 2023: 101278

  Abstract

  The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

  View details for DOI 10.1016/j.xcrm.2023.101278

  View details for PubMedID 37944529

• Transdifferentiation: A Novel Tool for Disease Modeling and Translational Applications in Alzheimer's Disease Chou, C., Vest, R., Prado, M. A., Wilson-Grady, J., Paulo, J. A., Shibuya, Y., Moran-Losada, P., Lee, T., Luo, J., Gygi, S. P., Kelly, J. W., Finley, D. P., Wernig, M., Wyss-Coray, T., Frydman, J. WILEY. 2023: S205-S206

  View details for Web of Science ID 001084474200356

• A role for Gpr37 in inflammation-induced dysmotility in the enteric nervous system Robertson, K., Hahn, O., Faruk, A., Hall, R., Wyss-Coray, T., Becker, L., Kaltschmidt, J. WILEY. 2023

  View details for Web of Science ID 001058584800297

• Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer's disease. Immunity Tsai, A. P., Dong, C., Lin, P. B., Oblak, A. L., Viana Di Prisco, G., Wang, N., Hajicek, N., Carr, A. J., Lendy, E. K., Hahn, O., Atkins, M., Foltz, A. G., Patel, J., Xu, G., Moutinho, M., Sondek, J., Zhang, Q., Mesecar, A. D., Liu, Y., Atwood, B. K., Wyss-Coray, T., Nho, K., Bissel, S. J., Lamb, B. T., Landreth, G. E. 2023

  Abstract

  Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.

  View details for DOI 10.1016/j.immuni.2023.08.008

  View details for PubMedID 37659412

• Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nature aging Park, C., Hahn, O., Gupta, S., Moreno, A. J., Marino, F., Kedir, B., Wang, D., Villeda, S. A., Wyss-Coray, T., Dubal, D. B. 2023

  Abstract

  Platelet factors regulate wound healing and can signal from the blood to the brain1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.

  View details for DOI 10.1038/s43587-023-00468-0

  View details for PubMedID 37587231

  View details for PubMedCentralID 4176932

• Atlas of the aging mouse brain reveals white matter as vulnerable foci. Cell Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., Zhang, H., Kaur, A., Hull, J., Huguenard, J. R., Grönke, S., Lehallier, B., Partridge, L., Keller, A., Wyss-Coray, T. 2023

  Abstract

  Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

  View details for DOI 10.1016/j.cell.2023.07.027

  View details for PubMedID 37591239

• APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia. bioRxiv : the preprint server for biology Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y. H., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., Wyss-Coray, T. 2023

  Abstract

  Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

  View details for DOI 10.1101/2023.07.21.549930

  View details for PubMedID 37546938

  View details for PubMedCentralID PMC10401952

• A 3' UTR Deletion Is a Leading Candidate Causal Variant at the TMEM106B Locus Reducing Risk for FTLD-TDP. medRxiv : the preprint server for health sciences Chemparathy, A., Le Guen, Y., Zeng, Y., Gorzynski, J., Jensen, T., Kasireddy, N., Talozzi, L., Belloy, M. E., Stewart, I., Gitler, A. D., Wagner, A. D., Mormino, E., Henderson, V. W., Wyss-Coray, T., Ashley, E., Greicius, M. D. 2023

  Abstract

  Single nucleotide variants (SNVs) near TMEM106B have been associated with risk of frontotemporal lobar dementia with TDP pathology (FTLD-TDP) but the causal variant at this locus has not yet been isolated. The initial leading FTLD-TDP genome-wide association study (GWAS) hit at this locus, rs1990622, is intergenic and is in linkage disequilibrium (LD) with a TMEM106B coding SNV, rs3173615. We developed a long-read sequencing (LRS) dataset of 407 individuals in order to identify structural variants associated with neurodegenerative disorders. We identified a prevalent 322 base pair deletion on the TMEM106B 3' untranslated region (UTR) that was in perfect linkage with rs1990622 and near-perfect linkage with rs3173615 (genotype discordance in two of 274 individuals who had LRS and short-read next-generation sequencing). In Alzheimer's Disease Sequencing Project (ADSP) participants, this deletion was in greater LD with rs1990622 (R2=0.920916, D'=0.963472) than with rs3173615 (R2=0.883776, D'=0.963575). rs1990622 and rs3173615 are less closely linked (R2=0.7403, D'=0.9915) in African populations. Among African ancestry individuals in the ADSP, the deletion is in even greater LD with rs1990622 (R2=0.936841, D'=0.976782) than with rs3173615 (R2=0.764242, D'=0.974406). Querying publicly available genetic datasets with associated mRNA expression and protein levels, we confirmed that rs1990622 is consistently a protein quantitative trait locus but not an expression quantitative trait locus, consistent with a causal variant present on the TMEM106B 3'UTR. In summary, the TMEM106B 3' UTR deletion is a large genetic variant on the TMEM106B transcript that is in higher LD with the leading GWAS hit rs1990622 than rs3173615 and may mediate the protective effect of this locus in neurodegenerative disease.

  View details for DOI 10.1101/2023.07.06.23292312

  View details for PubMedID 37461476

  View details for PubMedCentralID PMC10350161

• Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease. Science translational medicine Sung, Y. J., Yang, C., Norton, J., Johnson, M., Fagan, A., Bateman, R. J., Perrin, R. J., Morris, J. C., Farlow, M. R., Chhatwal, J. P., Schofield, P. R., Chui, H., Wang, F., Novotny, B., Eteleeb, A., Karch, C., Schindler, S. E., Rhinn, H., Johnson, E. C., Oh, H. S., Rutledge, J. E., Dammer, E. B., Seyfried, N. T., Wyss-Coray, T., Harari, O., Cruchaga, C. 2023; 15 (703): eabq5923

  Abstract

  Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.

  View details for DOI 10.1126/scitranslmed.abq5923

  View details for PubMedID 37406134

• Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease. Research square Cruchaga, C., Western, D., Timsina, J., Wang, L., Wang, C., Yang, C., Ali, M., Beric, A., Gorijala, P., Kohlfeld, P., Budde, J., Levey, A., Morris, J., Perrin, R., Ruiz, A., Marquié, M., Boada, M., de Rojas, I., Rutledge, J., Oh, H., Wilson, E., Guen, Y. L., Alvarez, I., Aguilar, M., Greicius, M., Pastor, P., Pulford, D., Ibanez, L., Wyss-Coray, T., Sung, Y. J., Phillips, B. 2023

  Abstract

  The integration of quantitative trait loci (QTL) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. QTL mapping has mainly been focused on multi-tissue expression QTL or plasma protein QTL (pQTL). Here we generated the largest-to-date cerebrospinal fluid (CSF) pQTL atlas by analyzing 7,028 proteins in 3,107 samples. We identified 3,373 independent study-wide associations for 1,961 proteins, including 2,448 novel pQTLs of which 1,585 are unique to CSF, demonstrating unique genetic regulation of the CSF proteome. In addition to the established chr6p22.2-21.32 HLA region, we identified pleiotropic regions on chr3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron-specificity and neurological development. We also integrated this pQTL atlas with the latest Alzheimer's disease (AD) GWAS through PWAS, colocalization and Mendelian Randomization and identified 42 putative causal proteins for AD, 15 of which have drugs available. Finally, we developed a proteomics-based risk score for AD that outperforms genetics-based polygenic risk scores. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits.

  View details for DOI 10.21203/rs.3.rs-2814616/v1

  View details for PubMedID 37333337

  View details for PubMedCentralID PMC10275048

• Effect of Aging Donors on Metabolic Signature and Cellular Senescence of Ipsc-derived Hepatocyte-Like Cells Kirchner, V. A., Badshah, J. S., Tak, E., Song, G., Kim, K., Krams, S. M., Wyss-Coray, T., Martinez, O., Lee, S., Niedernhofer, L. J., Tolar, J., Pruett, T. ELSEVIER SCIENCE INC. 2023: S929

  View details for Web of Science ID 001087126904056

• Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues. Nature biotechnology Wagner, V., Kern, F., Hahn, O., Schaum, N., Ludwig, N., Fehlmann, T., Engel, A., Henn, D., Rishik, S., Isakova, A., Tan, M., Sit, R., Neff, N., Hart, M., Meese, E., Quake, S., Wyss-Coray, T., Keller, A. 2023

  Abstract

  Molecular mechanisms of organismal and cell aging remain incompletely understood. We, therefore, generated a body-wide map of noncoding RNA (ncRNA) expression in aging (16 organs at ten timepoints from 1 to 27 months) and rejuvenated mice. We found molecular aging trajectories are largely tissue-specific except for eight broadly deregulated microRNAs (miRNAs). Their individual abundance mirrors their presence in circulating plasma and extracellular vesicles (EVs) whereas tissue-specific ncRNAs were less present. For miR-29c-3p, we observe the largest correlation with aging in solid organs, plasma and EVs. In mice rejuvenated by heterochronic parabiosis, miR-29c-3p was the most prominent miRNA restored to similar levels found in young liver. miR-29c-3p targets the extracellular matrix and secretion pathways, known to be implicated in aging. We provide a map of organism-wide expression of ncRNAs with aging and rejuvenation and identify a set of broadly deregulated miRNAs, which may function as systemic regulators of aging via plasma and EVs.

  View details for DOI 10.1038/s41587-023-01751-6

  View details for PubMedID 37106037

  View details for PubMedCentralID 3836174

• Activated immune cells drive neurodegeneration NATURE Guldner, I. H., Wyss-Coray, T. 2023; 615 (7953): 588-589

  View details for Web of Science ID 000961443400002

• Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation. bioRxiv : the preprint server for biology Marc-Daniel Mader, M., Napole, A., Wu, D., Shibuya, Y., Scavetti, A., Foltz, A., Atkins, M., Hahn, O., Yoo, Y., Danziger, R., Tan, C., Wyss-Coray, T., Steinman, L., Wernig, M. 2023

  Abstract

  Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

  View details for DOI 10.1101/2023.03.10.532123

  View details for PubMedID 36945385

  View details for PubMedCentralID PMC10028976

• Activated immune cells drive neurodegeneration in an Alzheimer's model. Nature Guldner, I. H., Wyss-Coray, T. 2023; 615 (7953): 588-589

  View details for DOI 10.1038/d41586-023-00600-5

  View details for PubMedID 36890310

• Sirtuin-2, NAD-Dependent Deacetylase, Is a New Potential Therapeutic Target for HIV-1 Infection and HIV-Related Neurological Dysfunction. Journal of virology Duran-Castells, C., Llano, A., Kawana-Tachikawa, A., Prats, A., Martinez-Zalacain, I., Kobayashi-Ishihara, M., Oriol-Tordera, B., Pena, R., Galvez, C., Silva-Arrieta, S., Clotet, B., Riveira-Munoz, E., Ballana, E., Prado, J. G., Martinez-Picado, J., Sanchez, J., Mothe, B., Hartigan-O'Connor, D., Wyss-Coray, T., Meyerhans, A., Gisslen, M., Price, R. W., Soriano-Mas, C., Munoz-Moreno, J. A., Brander, C., Ruiz-Riol, M. 2023: e0165522

  Abstract

  The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n=9) or delayed initiation (n=10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction.

  View details for DOI 10.1128/jvi.01655-22

  View details for PubMedID 36719240

• Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain. Nature aging Buckley, M. T., Sun, E. D., George, B. M., Liu, L., Schaum, N., Xu, L., Reyes, J. M., Goodell, M. A., Weissman, I. L., Wyss-Coray, T., Rando, T. A., Brunet, A. 2023; 3 (1): 121-137

  Abstract

  The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop 'aging clocks' based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions-heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.

  View details for DOI 10.1038/s43587-022-00335-4

  View details for PubMedID 37118510

• Ageing-associated small RNA cargo of extracellular vesicles. RNA biology Kern, F., Kuhn, T., Ludwig, N., Simon, M., Groger, L., Fabis, N., Aparicio-Puerta, E., Salhab, A., Fehlmann, T., Hahn, O., Engel, A., Wagner, V., Koch, M., Winek, K., Soreq, H., Nazarenko, I., Fuhrmann, G., Wyss-Coray, T., Meese, E., Keller, V., Laschke, M. W., Keller, A. 2023; 20 (1): 482-494

  Abstract

  Previous work on murine models and humans demonstrated global as well as tissue-specific molecular ageing trajectories of RNAs. Extracellular vesicles (EVs) are membrane vesicles mediating the horizontal transfer of genetic information between different tissues. We sequenced small regulatory RNAs (sncRNAs) in two mouse plasma fractions at five time points across the lifespan from 2-18months: (1) sncRNAs that are free-circulating (fc-RNA) and (2) sncRNAs bound outside or inside EVs (EV-RNA). Different sncRNA classes exhibit unique ageing patterns that vary between the fcRNA and EV-RNA fractions. While tRNAs showed the highest correlation with ageing in both fractions, rRNAs exhibited inverse correlation trajectories between the EV- and fc-fractions. For miRNAs, the EV-RNA fraction was exceptionally strongly associated with ageing, especially the miR-29 family in adipose tissues. Sequencing of sncRNAs and coding genes in fat tissue of an independent cohort of aged mice up to 27months highlighted the pivotal role of miR-29a-3p and miR-29b-3p in ageing-related gene regulation that we validated in a third cohort by RT-qPCR.

  View details for DOI 10.1080/15476286.2023.2234713

  View details for PubMedID 37498213

• LARGE-SCALE IN VIVO CRISPR SCREENS IDENTIFY SAGA COMPLEX MEMBERS AS KEY REGULATORS OF HAEMATOPOIESIS Wilkinson, A., Haney, M., Shankar, A., Hsu, I., Miyauchi, M., Palovics, R., Olender, L., Khoo, H., Igarashi, K., Bhadury, J., Munson, C., Mack, P., Tan, T., Nakauchi, H., Wyss-Coray, T. ELSEVIER SCIENCE INC. 2023: S43

  View details for Web of Science ID 001057881700032

• Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain NATURE AGING Buckley, M. T., Sun, E. D., George, B. M., Liu, L., Schaum, N., Xu, L., Reyes, J. M., Goodell, M. A., Weissman, I. L., Wyss-Coray, T., Rando, T. A., Brunet, A. 2023; 3 (1): 121-+

  View details for DOI 10.1038/s43587-022-00335-4

  View details for Web of Science ID 000922722500016

• Author Correction: Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature Iram, T., Kern, F., Kaur, A., Myneni, S., Morningstar, A. R., Shin, H., Garcia, M. A., Yerra, L., Palovics, R., Yang, A. C., Hahn, O., Lu, N., Shuken, S. R., Haney, M. S., Lehallier, B., Iyer, M., Luo, J., Zetterberg, H., Keller, A., Zuchero, J. B., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s41586-022-05630-z

  View details for PubMedID 36513761

• Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H., Losada, P. M., Rutledge, J., Trelle, A. N., Mormino, E. C., Elahi, F., Galasko, D. R., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Gate, D. 2022

  Abstract

  Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 Tcells. Clonal CD8T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific Tcell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

  View details for DOI 10.1016/j.cell.2022.11.019

  View details for PubMedID 36516855

• GhostKnockoff inference empowers identification of putative causal variants in genome-wide association studies. Nature communications He, Z., Liu, L., Belloy, M. E., Le Guen, Y., Sossin, A., Liu, X., Qi, X., Ma, S., Gyawali, P. K., Wyss-Coray, T., Tang, H., Sabatti, C., Candes, E., Greicius, M. D., Ionita-Laza, I. 2022; 13 (1): 7209

  Abstract

  Recent advances in genome sequencing and imputation technologies provide an exciting opportunity to comprehensively study the contribution of genetic variants to complex phenotypes. However, our ability to translate genetic discoveries into mechanistic insights remains limited at this point. In this paper, we propose an efficient knockoff-based method, GhostKnockoff, for genome-wide association studies (GWAS) that leads to improved power and ability to prioritize putative causal variants relative to conventional GWAS approaches. The method requires only Z-scores from conventional GWAS and hence can be easily applied to enhance existing and future studies. The method can also be applied to meta-analysis of multiple GWAS allowing for arbitrary sample overlap. We demonstrate its performance using empirical simulations and two applications: (1) a meta-analysis for Alzheimer's disease comprising nine overlapping large-scale GWAS, whole-exome and whole-genome sequencing studies and (2) analysis of 1403 binary phenotypes from the UK Biobank data in 408,961 samples of European ancestry. Our results demonstrate that GhostKnockoff can identify putatively functional variants with weaker statistical effects that are missed by conventional association tests.

  View details for DOI 10.1038/s41467-022-34932-z

  View details for PubMedID 36418338

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• An automated feeding system for the African killifish reveals effects of dietary restriction on lifespan and allows scalable assessment of associative learning. eLife McKay, A., Costa, E. K., Chen, J., Hu, C., Chen, X., Bedbrook, C. N., Khondker, R. C., Thielvoldt, M., Priya Singh, P., Wyss-Coray, T., Brunet, A. 2022; 11

  Abstract

  The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof-of-concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.

  View details for DOI 10.7554/eLife.69008

  View details for PubMedID 36354233

• Microglia states and nomenclature: A field at its crossroads. Neuron Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M. E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., Bennett, F., Bessis, A., Biber, K., Bilbo, S., Blurton-Jones, M., Boddeke, E., Brites, D., Brône, B., Brown, G. C., Butovsky, O., Carson, M. J., Castellano, B., Colonna, M., Cowley, S. A., Cunningham, C., Davalos, D., De Jager, P. L., de Strooper, B., Denes, A., Eggen, B. J., Eyo, U., Galea, E., Garel, S., Ginhoux, F., Glass, C. K., Gokce, O., Gomez-Nicola, D., González, B., Gordon, S., Graeber, M. B., Greenhalgh, A. D., Gressens, P., Greter, M., Gutmann, D. H., Haass, C., Heneka, M. T., Heppner, F. L., Hong, S., Hume, D. A., Jung, S., Kettenmann, H., Kipnis, J., Koyama, R., Lemke, G., Lynch, M., Majewska, A., Malcangio, M., Malm, T., Mancuso, R., Masuda, T., Matteoli, M., McColl, B. W., Miron, V. E., Molofsky, A. V., Monje, M., Mracsko, E., Nadjar, A., Neher, J. J., Neniskyte, U., Neumann, H., Noda, M., Peng, B., Peri, F., Perry, V. H., Popovich, P. G., Pridans, C., Priller, J., Prinz, M., Ragozzino, D., Ransohoff, R. M., Salter, M. W., Schaefer, A., Schafer, D. P., Schwartz, M., Simons, M., Smith, C. J., Streit, W. J., Tay, T. L., Tsai, L. H., Verkhratsky, A., von Bernhardi, R., Wake, H., Wittamer, V., Wolf, S. A., Wu, L. J., Wyss-Coray, T. 2022; 110 (21): 3458-3483

  Abstract

  Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

  View details for DOI 10.1016/j.neuron.2022.10.020

  View details for PubMedID 36327895

• Microglia states and nomenclature: A field at its crossroads NEURON Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., Bennett, F., Bessis, A., Biber, K., Bilbo, S., Blurton-Jones, M., Boddeke, E., Brites, D., Brone, B., Brown, G. C., Butovsky, O., Carson, M. J., Castellano, B., Colonna, M., Cowley, S. A., Cunningham, C., Davalos, D., De Jager, P. L., de Strooper, B., Denes, A., Eggen, B. L., Eyo, U., Galea, E., Garel, S., Ginhoux, F., Glass, C. K., Gokce, O., Gomez-Nicola, D., Gonzalez, B., Gordon, S., Graeber, M. B., Greenhalgh, A. D., Gressens, P., Greter, M., Gutmann, D. H., Haass, C., Heneka, M. T., Heppner, F. L., Hong, S., Hume, D. A., Jung, S., Kettenmann, H., Kipnis, J., Koyama, R., Lemke, G., Lynch, M., Majewska, A., Malcangio, M., Malm, T., Mancuso, R., Masuda, T., Matteoli, M., McColl, B. W., Miron, V. E., Molofsky, A., Monje, M., Mracsko, E., Nadjar, A., Neher, J. J., Neniskyte, U., Neumann, H., Noda, M., Peng, B., Peri, F., Perry, V., Popovich, P. G., Pridans, C., Priller, J., Prinz, M., Ragozzino, D., Ransohoff, R. M., Salter, M. W., Schaefer, A., Schafer, D. P., Schwartz, M., Simons, M., Smith, C. J., Streit, W. J., Tuan Leng Tay, Tsai, L., Verkhratsky, A., von Bernhardi, R., Wake, H., Wittamer, V., Wolf, S. A., Wu, L., Wyss-Coray, T. 2022; 110 (21): 3458-3483

  View details for Web of Science ID 000915789000010

• Transcriptomic Profiling Identifies CD8+ T Cells in the Brain of Aged and Alzheimer's Disease Transgenic Mice as Tissue-Resident Memory T Cells. Journal of immunology (Baltimore, Md. : 1950) Altendorfer, B., Unger, M. S., Poupardin, R., Hoog, A., Asslaber, D., Gratz, I. K., Mrowetz, H., Benedetti, A., Bessa de Sousa, D. M., Greil, R., Egle, A., Gate, D., Wyss-Coray, T., Aigner, L. 2022

  Abstract

  Peripheral immune cell infiltration into the brain is a prominent feature in aging and various neurodegenerative diseases such as Alzheimer's disease (AD). As AD progresses, CD8+ T cells infiltrate into the brain parenchyma, where they tightly associate with neurons and microglia. The functional properties of CD8+ T cells in the brain are largely unknown. To gain further insights into the putative functions of CD8+ T cells in the brain, we explored and compared the transcriptomic profile of CD8+ T cells isolated from the brain and blood of transgenic AD (APPswe/PSEN1dE9, line 85 [APP-PS1]) and age-matched wild-type (WT) mice. Brain CD8+ T cells of APP-PS1 and WT animals had similar transcriptomic profiles and substantially differed from blood circulating CD8+ T cells. The gene signature of brain CD8+ T cells identified them as tissue-resident memory (Trm) T cells. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis on the significantly upregulated genes revealed overrepresentation of biological processes involved in IFN-beta signaling and the response to viral infections. Furthermore, brain CD8+ T cells of APP-PS1 and aged WT mice showed similar differentially regulated genes as brain Trm CD8+ T cells in mouse models with acute virus infection, chronic parasite infection, and tumor growth. In conclusion, our profiling of brain CD8+ T cells suggests that in AD, these cells exhibit similar adaptive immune responses as in other inflammatory diseases of the CNS, potentially opening the door for immunotherapy in AD.

  View details for DOI 10.4049/jimmunol.2100737

  View details for PubMedID 36165202

• Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling. Stem cell reviews and reports Argouarch, A. R., Schultz, N., Yang, A. C., Jang, Y., Garcia, K., Cosme, C. G., Corrales, C. I., Nana, A. L., Karydas, A. M., Spina, S., Grinberg, L. T., Miller, B., Wyss-Coray, T., Abyzov, A., Goodarzi, H., Seeley, W. W., Kao, A. W. 2022

  Abstract

  Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols has not been fully established. In this study, cells derived from postmortem dura mater are directly compared to those from dermal biopsies of living subjects. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences were observed between cells of dermal and dural origin. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, slower growth rates, and a higher rate of karyotype abnormality. Dura mater-derived cells also failed to express fibroblast protein markers. When dermal fibroblasts and dura mater-derived cells from the same subject were compared, they exhibited highly divergent gene expression profiles that suggest dura mater cells originated from a mixed mural lineage. Given their postmortem origin, somatic mutation signatures of dura mater-derived cells were assessed and suggest defective DNA damage repair. This study argues for rigorous karyotyping of postmortem derived cell lines and highlights limitations of postmortem human dura mater-derived cells for modeling normal biology or disease-associated pathobiology.

  View details for DOI 10.1007/s12015-022-10416-x

  View details for PubMedID 35809166

• An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer's disease. Nature aging Jiang, Y., Zhou, X., Wong, H. Y., Ouyang, L., Ip, F. C., Chau, V. M., Lau, S. F., Wu, W., Wong, D. Y., Seo, H., Fu, W. Y., Lai, N. C., Chen, Y., Chen, Y., Tong, E. P., Mok, V. C., Kwok, T. C., Mok, K. Y., Shoai, M., Lehallier, B., Losada, P. M., O'Brien, E., Porter, T., Laws, S. M., Hardy, J., Wyss-Coray, T., Masters, C. L., Fu, A. K., Ip, N. Y. 2022; 2 (7): 616-634

  Abstract

  Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.

  View details for DOI 10.1038/s43587-022-00241-9

  View details for PubMedID 37117777

  View details for PubMedCentralID 5958625

• Structural changes in cerebrospinal fluid proteins are associated with brain aging (Vol 2, pg 375, 2022) NATURE AGING Shuken, S. R., Wyss-Coray, T. 2022; 2 (7): 679

  View details for DOI 10.1038/s43587-022-00254-4

  View details for Web of Science ID 000926963600015

  View details for PubMedID 37253872

• An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-epsilon 4 in female patients with Alzheimer's disease NATURE AGING Jiang, Y., Zhou, X., Wong, H., Ouyang, L., Ip, F. F., Chau, V. N., Lau, S., Wu, W., Wong, D. K., Seo, H., Fu, W., Lai, N. H., Chen, Y., Chen, Y., Tong, E. S., Mok, V. T., Kwok, T. Y., Mok, K. Y., Shoai, M., Lehallier, B., Losada, P., O'Brien, E., Porter, T., Laws, S. M., Hardy, J., Wyss-Coray, T., Masters, C. L., Fu, A. Y., Ip, N. Y., Alzheimer's Dis Neuroimaging Initi 2022; 2 (7): 616-+

  View details for DOI 10.1038/s43587-022-00241-9

  View details for Web of Science ID 000916579000013

• Unraveling protein dynamics to understand the brain - the next molecular frontier. Molecular neurodegeneration Brewer, K. D., Shi, S. M., Wyss-Coray, T. 2022; 17 (1): 45

  Abstract

  The technological revolution to measure global gene expression at the single-cell level is currently transforming our knowledge of the brain and neurological diseases, leading from a basic understanding of genetic regulators and risk factors to one of more complex gene interactions and biological pathways. Looking ahead, our next challenge will be the reliable measurement and understanding of proteins. We describe in this review how to apply new, powerful methods of protein labeling, tracking, and detection. Recent developments of these methods now enable researchers to uncover protein mechanisms in vivo that may previously have only been hypothesized. These methods are also useful for discovering new biology because how proteins regulate systemic interactions is not well understood in most cases, such as how they travel through the bloodstream to distal targets or cross the blood-brain barrier. Genetic sequencing of DNA and RNA have enabled many great discoveries in the past 20years, and now, the protein methods described here are creating a more complete picture of how cells to whole organisms function. It is likely that these developments will generate another transformation in biomedical research and our understanding of the brain and will ultimately allow for patient-specific medicine on a protein level.

  View details for DOI 10.1186/s13024-022-00546-8

  View details for PubMedID 35717317

• Measuring biological age using omics data. Nature reviews. Genetics Rutledge, J., Oh, H., Wyss-Coray, T. 2022

  Abstract

  Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.

  View details for DOI 10.1038/s41576-022-00511-7

  View details for PubMedID 35715611

• The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (New York, N.Y.) Jones, R. C., Karkanias, J., Krasnow, M. A., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Pisco, A. O., Tan, S. Y., Travaglini, K. J., Xu, C., Alcántara-Hernández, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Crasta, S., Culver, R. N., Cvijović, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kolluru, S., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W. J., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Morri, M., Mrouj, K., Mukherjee, S., Muser, T., Neuhöfer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Pisco, A. O., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L. C., Subramaniam, V. R., Swarup, A., Swift, M., Travaglini, K. J., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgó, E., Martin, B. A., Ozawa, M. G., Silva, O., Tan, S. Y., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Detweiler, A. M., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., de Morree, A., Olivieri, J. E., Park, M., Pisco, A. O., Ravikumar, N., Salzman, J., Stanley, G., Swift, M., Tan, M., Tan, W., Tarashansky, A. J., Vanheusden, R., Vorperian, S. K., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Alcántara-Hernández, M., Antony, J., Chan, C. K., Chang, C. A., Colville, A., Crasta, S., Culver, R., Dethlefsen, L., Ezran, C., Gillich, A., Hang, Y., Ho, P. Y., Irwin, J. C., Jang, S., Kershner, A. M., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Liu, S., Loeb, G. B., Lu, W. J., Maltzman, J. S., Metzger, R. J., de Morree, A., Neuhöfer, P., Perez, K., Phansalkar, R., Qi, Z., Rao, P., Raquer-McKay, H., Sasagawa, K., Scott, B., Sinha, R., Song, H., Spencer, S. P., Swarup, A., Swift, M., Travaglini, K. J., Trimm, E., Veizades, S., Vijayakumar, S., Wang, B., Wang, W., Winkler, J., Xie, J., Yung, A. R., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Krasnow, M., Kuo, C. S., Nguyen, P., Quake, S. R., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wang, B., Wu, A., Wu, S. M., Wyss-Coray, T. 2022; 376 (6594): eabl4896

  Abstract

  Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

  View details for DOI 10.1126/science.abl4896

  View details for PubMedID 35549404

• Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17. Nature Iram, T., Kern, F., Kaur, A., Myneni, S., Morningstar, A. R., Shin, H., Garcia, M. A., Yerra, L., Palovics, R., Yang, A. C., Hahn, O., Lu, N., Shuken, S. R., Haney, M. S., Lehallier, B., Iyer, M., Luo, J., Zetterberg, H., Keller, A., Zuchero, J. B., Wyss-Coray, T. 2022

  Abstract

  Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

  View details for DOI 10.1038/s41586-022-04722-0

  View details for PubMedID 35545674

• Publisher Correction: Limited proteolysis-mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures. Nature aging Shuken, S. R., Rutledge, J., Iram, T., Losada, P. M., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022; 2 (5): 455

  View details for DOI 10.1038/s43587-022-00225-9

  View details for PubMedID 37118077

• Limited proteolysis-mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures (vol 2, pg 379, 2022) NATURE AGING Shuken, S. R., Rutledge, J., Iram, T., Losada, P., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022; 2 (5): 455

  View details for DOI 10.1038/s43587-022-00225-9

  View details for Web of Science ID 000916578300018

• Structural changes in cerebrospinal fluid proteins are associated with brain aging NATURE AGING Shuken, S. R., Wyss-Coray, T. 2022; 2 (5): 375-376

  View details for DOI 10.1038/s43587-022-00213-z

  View details for Web of Science ID 000916578300008

• KL1 domain of longevity factor klotho mimics the metabolome of cognitive stimulation and enhances cognition in young and aging mice. The Journal of neuroscience : the official journal of the Society for Neuroscience Gupta, S., Moreno, A. J., Wang, D., Leon, J., Chen, C., Hahn, O., Poon, Y., Greenberg, K., David, N., Wyss-Coray, T., Raftery, D., Promislow, D. E., Dubal, D. B. 2022

  Abstract

  Cognitive deficits are a major biomedical challenge - and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biologic effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus - and that pharmacologic treatment with the longevity hormone alpha-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a close metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENTCognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognition. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain - and provide a plausible therapeutic intervention for mimicking these alterations, that in turn, improves cognition in the young and aging brain.

  View details for DOI 10.1523/JNEUROSCI.2458-21.2022

  View details for PubMedID 35428698

• Publisher Correction: Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s41587-022-01293-3

  View details for PubMedID 35347330

• Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America Vest, R. T., Chou, C. C., Zhang, H., Haney, M. S., Li, L., Laqtom, N. N., Chang, B., Shuken, S., Nguyen, A., Yerra, L., Yang, A. C., Green, C., Tanga, M., Abu-Remaileh, M., Bassik, M. C., Frydman, J., Luo, J., Wyss-Coray, T. 2022; 119 (11): e2121609119

  Abstract

  SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts. In this work, we find that the antiinflammatory and neuroprotective compound, discovered via a phenotypic screen, imparts its beneficial effects by targeting the lysosome and restoring its function. This is established using a genome-wide CRISPRi target identification screen and then confirmed using a variety of lysosome-targeted studies. The resulting small molecule from this study represents a potential treatment for neurodegenerative diseases as well as a research tool for the study of lysosomes in disease.

  View details for DOI 10.1073/pnas.2121609119

  View details for PubMedID 35259016

• Molecular hallmarks of heterochronic parabiosis at single-cell resolution. Nature Palovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., Tabula Muris Consortium, Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., Wyss-Coray, T., Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gomez-Sjoberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J. 2022

  Abstract

  The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

  View details for DOI 10.1038/s41586-022-04461-2

  View details for PubMedID 35236985

• A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature Yang, A. C., Vest, R. T., Kern, F., Lee, D. P., Agam, M., Maat, C. A., Losada, P. M., Chen, M. B., Schaum, N., Khoury, N., Toland, A., Calcuttawala, K., Shin, H., Palovics, R., Shin, A., Wang, E. Y., Luo, J., Gate, D., Schulz-Schaeffer, W. J., Chu, P., Siegenthaler, J. A., McNerney, M. W., Keller, A., Wyss-Coray, T. 2022

  Abstract

  The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's diseaserisk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

  View details for DOI 10.1038/s41586-021-04369-3

  View details for PubMedID 35165441

• Molecular map of the human blood-brain barrier reveals links to Alzheimer's disease NATURE Vest, R. T., Wyss-Coray, T. 2022

  View details for DOI 10.1038/d41586-022-00350-w

  View details for Web of Science ID 000755020600002

  View details for PubMedID 35165406

• Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  Abstract

  Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

  View details for DOI 10.1038/s41587-021-01188-9

  View details for PubMedID 35132263

• Corrigendum: Long-Term Cognitive Impairments and Pathological Alterations in a Mouse Model of Repetitive Mild Traumatic Brain Injury. Frontiers in neurology Luo, J., Nguyen, A., Villeda, S., Zhang, H., Ding, Z., Lindsey, D., Bieri, G., Castellano, J. M., Beaupre, G. S., Wyss-Coray, T. 2022; 13: 730576

  Abstract

  [This corrects the article DOI: 10.3389/fneur.2014.00012.].

  View details for DOI 10.3389/fneur.2022.730576

  View details for PubMedID 35847232

• Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures Nature Aging Shuken, S. R., Rutledge, J., Iram, T., Moran Losada, P., Wilson, E. N., Andreasson, K. I., Leib, R. D., Wyss-Coray, T. 2022

  View details for DOI 10.1038/s43587-022-00196-x

• Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration Proc Natl Acad Sci U S A . Vest*, R. T., Chou*, C., Zhang, H., Haney, M. S., Li, L., Laqtom, N. N., Chang, B., Shuken, S., Nguyen, A., Yerra, L., Yang, A. C., Green, C., Tanga, M., Abu-Remaileh, M., Bassik, M. C., Frydman, J., Luo, J., Wyss-Coray, T. 2022; 119 (11): e2121609119

  View details for DOI 10.1073/pnas.2121609119

• Treatment of a genetic brain disease by CNS-wide microglia replacement. Science translational medicine Shibuya, Y., Kumar, K. K., Mader, M. M., Yoo, Y., Ayala, L. A., Zhou, M., Mohr, M. A., Neumayer, G., Kumar, I., Yamamoto, R., Marcoux, P., Liou, B., Bennett, F. C., Nakauchi, H., Sun, Y., Chen, X., Heppner, F. L., Wyss-Coray, T., Südhof, T. C., Wernig, M. 2022; 14 (636): eabl9945

  Abstract

  Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

  View details for DOI 10.1126/scitranslmed.abl9945

  View details for PubMedID 35294256

• Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature De Miguel, Z., Khoury, N., Betley, M. J., Lehallier, B., Willoughby, D., Olsson, N., Yang, A. C., Hahn, O., Lu, N., Vest, R. T., Bonanno, L. N., Yerra, L., Zhang, L., Saw, N. L., Fairchild, J. K., Lee, D., Zhang, H., McAlpine, P. L., Contrepois, K., Shamloo, M., Elias, J. E., Rando, T. A., Wyss-Coray, T. 2021

  Abstract

  Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration1. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus2-4, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.

  View details for DOI 10.1038/s41586-021-04183-x

  View details for PubMedID 34880498

• Targeting VCAM1 to reduce neuroinflammation in ischemia-triggered vascular dementia. Alzheimer's & dementia : the journal of the Alzheimer's Association Zera, K. A., Peterson, T., Yousef, H., Lee, D., Wyss-Coray, T., Buckwalter, M. S. 1800; 17 Suppl 3: e053849

  Abstract

  BACKGROUND: Ischemia is a well-established contributor to vascular dementia. Indeed, the most common pathology in people with dementia is mixed, and over half of patients diagnosed with AD have demonstrable vascular pathologies. Ischemia induces an immune response which triggers secondary neurodegeneration remote to the initial lesion, and consequent cognitive decline. Ischemia-triggered vascular dementia is dependent on B-lymphocytes driving chronic neuroinflammation in adult mice. However, vascular dementia is most common in the aged, and there are key differences in inflammatory responses with age. Vascular cell adhesion molecule 1 (VCAM1) is an endothelial protein that facilitates vascular-immune crosstalk via interaction with very late antigen-4 (VLA-4). Soluble VCAM1 is elevated in stroke, vascular dementia, and normal aging in both people and mice. In aging mice, anti-VCAM1 ameliorates age-induced neuroinflammation and cognitive impairment. Although the mechanism is unclear, this is likely mediated via changes in endothelial cell activation and secretion of pro-inflammatory mediators. Therefore, we hypothesized that acute anti-VCAM1 treatment would reduce microgliosis and astrogliosis, while delayed treatment would reduce B and T lymphocyte infiltration in a mouse model of ischemia-triggered vascular dementia.METHOD: Adult (3-month-old) or aged (10-month-old) C57BL/6J mice (n=10-15/group) underwent permanent distal middle cerebral artery occlusion. Mice were dosed with anti-VCAM1 antibody either 4 hours or 4 days post-ischemia, and then sacrificed at 72 hours, 3 weeks or 6 weeks post-ischemia. Microgliosis and astrogliosis were quantified as percent area immunostained in the lesion border by CD68 and GFAP, respectively. B and T cell infiltration were quantified as percent lesion immunostained by B220, and CD3+ cells in the ischemic lesion, respectively.RESULT: Acute treatment reduced microgliosis 30% (p=0.0476) and astrogliosis 39% (p<0.03). In adults, delayed anti-VCAM1 significantly reduced B and T cell infiltration approximately 25% (p=0.0015) and 50% (p=0.0192), respectively. Similarly, in aged mice, delayed anti-VCAM1 significantly reduced B and T cell infiltration approximately 50% (p=0.0037) and 30% (p=0.0036), respectively. In contrast, early anti-VCAM1 had little or no effect on B or T cell infiltration.CONCLUSION: Together, these findings establish VCAM1 as a possible therapeutic target to ameliorate ischemia-induced neuroinflammation and consequent cognitive decline in a mouse model of vascular dementia.

  View details for DOI 10.1002/alz.053849

  View details for PubMedID 35108898

• An oligomeric semiconducting nanozyme with ultrafast electron transfers alleviates acute brain injury. Science advances Mu, X., Wang, J., He, H., Li, Q., Yang, B., Wang, J., Liu, H., Gao, Y., Ouyang, L., Sun, S., Ren, Q., Shi, X., Hao, W., Fei, Q., Yang, J., Li, L., Vest, R., Wyss-Coray, T., Luo, J., Zhang, X. 2021; 7 (46): eabk1210

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/sciadv.abk1210

  View details for PubMedID 34757781

• CD4+ T cells contribute to neurodegeneration in Lewy body dementia. Science (New York, N.Y.) Gate, D., Tapp, E., Leventhal, O., Shahid, M., Nonninger, T. J., Yang, A. C., Strempfl, K., Unger, M. S., Fehlmann, T., Oh, H., Channappa, D., Henderson, V. W., Keller, A., Aigner, L., Galasko, D. R., Davis, M. M., Poston, K. L., Wyss-Coray, T. 2021: eabf7266

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/science.abf7266

  View details for PubMedID 34648304

• Dysregulation of brain and choroid plexus cell types in severe COVID-19 (vol 595, pg 565, 2021) NATURE Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M., Channappa, D., Cobos, I., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., Wyss-Coray, T. 2021

  View details for DOI 10.1038/s41586-021-04080-3

  View details for Web of Science ID 000704968600001

  View details for PubMedID 34625744

  View details for PubMedCentralID PMC8500262

• miRNATissueAtlas2: an update to the human miRNA tissue atlas. Nucleic acids research Keller, A., Groger, L., Tschernig, T., Solomon, J., Laham, O., Schaum, N., Wagner, V., Kern, F., Schmartz, G. P., Li, Y., Borcherding, A., Meier, C., Wyss-Coray, T., Meese, E., Fehlmann, T., Ludwig, N. 2021

  Abstract

  Small non-coding RNAs (sncRNAs) are pervasive regulators of physiological and pathological processes. We previously developed the human miRNA Tissue Atlas, detailing the expression of miRNAs across organs in the human body. Here, we present an updated resource containing sequencing data of 188 tissue samples comprising 21 organ types retrieved from six humans. Sampling the organs from the same bodies minimizes intra-individual variability and facilitates the making of a precise high-resolution body map of the non-coding transcriptome. The data allow shedding light on the organ- and organ system-specificity of piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs) and other non-coding RNAs. As use case of our resource, we describe the identification of highly specific ncRNAs in different organs. The update also contains 58 samples from six tissues of the Tabula Muris collection, allowing to check if the tissue specificity is evolutionary conserved between Homo sapiens and Mus musculus. The updated resource of 87252 non-coding RNAs from nine non-coding RNA classes for all organs and organ systems is available online without any restrictions (https://www.ccb.uni-saarland.de/tissueatlas2).

  View details for DOI 10.1093/nar/gkab808

  View details for PubMedID 34570238

• RNA splicing programs define tissue compartments and cell types at single-cell resolution ELIFE Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10

  View details for DOI 10.7554/eLife.70692.sa2

  View details for Web of Science ID 000715795700001

• Author Correction: An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature aging Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S. S., Maecker, H. T., Dekker, C. L., Wyss-Coray, T., Franceschi, C., Jojic, V., Haddad, F., Montoya, J. G., Wu, J. C., Davis, M. M., Furman, D. 2021; 1 (8): 748

  View details for DOI 10.1038/s43587-021-00102-x

  View details for PubMedID 37117770

• Peripheral B-cells repress B-cell regeneration in aging through a TNFalpha/IGFBP-1/IGF1 immune-endocrine axis. Blood Dowery, R., Benhamou, D., Benchetrit, E., Harel, O., Nevelsky, A., Zisman-Rozen, S., Braun-Moscovici, Y., Balbir-Gurman, A., Avivi, I., Shechter, A., Berdnik, D., Wyss-Coray, T., Melamed, D. 2021

  Abstract

  Loss of B lymphocyte regeneration in the bone marrow (BM) is an immunological hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, thereby contributing to immune system dysfunction associated with aging. A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. In the present work, we uncover an immune-endocrine regulatory circuit that mediates cross-talk between peripheral B-cells and progenitors in the BM, to balance B-lymphopoiesis in both human and mouse aging. We found that tumor necrosis factor alpha (TNFalpha), which is highly produced by peripheral B-cells in aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds and sequesters insulin-like growth factor 1 (IGF1) in the circulation, thereby restraining its activity in promoting B-lymphopoiesis in the BM. Upon B-cell depletion in aged humans and mice, circulatory TNFalpha decreases, resulting in increased IGF1 and reactivation of B-lymphopoiesis. Perturbation of this circuit by administration of IGF1 to old mice or anti-TNFa antibodies to human patients restored B-lymphopoiesis in the BM. Hence, we suggest that in both human and mouse aging, peripheral B-cells utilize the TNFalpha/IGFBP-1/IGF1 axis to repress B-lymphopoiesis.

  View details for DOI 10.1182/blood.2021012428

  View details for PubMedID 34297797

• An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature aging Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S. S., Maecker, H. T., Dekker, C. L., Wyss-Coray, T., Franceschi, C., Jojic, V., Haddad, F., Montoya, J. G., Wu, J. C., Davis, M. M., Furman, D. 2021; 1: 598-615

  Abstract

  While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

  View details for DOI 10.1038/s43587-021-00082-y

  View details for PubMedID 34888528

• Dysregulation of brain and choroid plexus cell types in severe COVID-19. Nature Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., Calcuttawala, K., Vest, R. T., Berdnik, D., Lu, N., Hahn, O., Gate, D., McNerney, M. W., Channappa, D., Cobos, I., Ludwig, N., Schulz-Schaeffer, W. J., Keller, A., Wyss-Coray, T. 2021

  Abstract

  Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1-3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4-6. Synaptic signaling of upper-layer excitatory neurons-evolutionarily expanded in humans7 and linked to cognitive function8-are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.

  View details for DOI 10.1038/s41586-021-03710-0

  View details for PubMedID 34153974

• Aging and Rejuvenation of Oligodendrocytes Iram, T., Kern, F., Kaur, A., Myneni, S., Garcia, M., Yerra, L., Lou, J., Zetterberg, H., Keller, A., Zuchero, J., Wyss-Coray, T. SAGE PUBLICATIONS LTD. 2021: 5-6

  View details for Web of Science ID 000669008200010

• Deep sequencing of sncRNAs reveals hallmarks and regulatory modules of the transcriptome during Parkinson's disease progression. Nature aging Kern, F., Fehlmann, T., Violich, I., Alsop, E., Hutchins, E., Kahraman, M., Grammes, N. L., Guimarães, P., Backes, C., Poston, K. L., Casey, B., Balling, R., Geffers, L., Krüger, R., Galasko, D., Mollenhauer, B., Meese, E., Wyss-Coray, T., Craig, D. W., Van Keuren-Jensen, K., Keller, A. 2021; 1 (3): 309-322

  Abstract

  Noncoding RNAs have diagnostic and prognostic importance in Parkinson's disease (PD). We studied circulating small noncoding RNAs (sncRNAs) in two large-scale longitudinal PD cohorts (Parkinson's Progression Markers Initiative (PPMI) and Luxembourg Parkinson's Study (NCER-PD)) and modeled their impact on the transcriptome. Sequencing of sncRNAs in 5,450 blood samples of 1,614 individuals in PPMI yielded 323 billion reads, most of which mapped to microRNAs but covered also other RNA classes such as piwi-interacting RNAs, ribosomal RNAs and small nucleolar RNAs. Dysregulated microRNAs associated with disease and disease progression occur in two distinct waves in the third and seventh decade of life. Originating predominantly from immune cells, they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. Profiling 1,553 samples from 1,024 individuals in the NCER-PD cohort validated biomarkers and main findings by an independent technology. Finally, network analysis of sncRNA and transcriptome sequencing from PPMI identified regulatory modules emerging in patients with progressing PD.

  View details for DOI 10.1038/s43587-021-00042-6

  View details for PubMedID 37118411

  View details for PubMedCentralID 2930111

• A neuronal blood marker is associated with mortality in old age. Nature aging Kaeser, S. A., Lehallier, B., Thinggaard, M., Häsler, L. M., Apel, A., Bergmann, C., Berdnik, D., Jeune, B., Christensen, K., Grönke, S., Partridge, L., Wyss-Coray, T., Mengel-From, J., Jucker, M. 2021; 1 (2): 218-225

  Abstract

  Neurofilament light chain (NfL) has emerged as a promising blood biomarker for the progression of various neurological diseases. NfL is a structural protein of nerve cells, and elevated NfL levels in blood are thought to mirror damage to the nervous system. We find that plasma NfL levels increase in humans with age (n = 122; 21-107 years of age) and correlate with changes in other plasma proteins linked to neural pathways. In centenarians (n = 135), plasma NfL levels are associated with mortality equally or better than previously described multi-item scales of cognitive or physical functioning, and this observation was replicated in an independent cohort of nonagenarians (n = 180). Plasma NfL levels also increase in aging mice (n = 114; 2-30 months of age), and dietary restriction, a paradigm that extends lifespan in mice, attenuates the age-related increase in plasma NfL levels. These observations suggest a contribution of nervous system functional deterioration to late-life mortality.

  View details for DOI 10.1038/s43587-021-00028-4

  View details for PubMedID 37118632

  View details for PubMedCentralID 3756938

• Methods to investigate intrathecal adaptive immunity in neurodegeneration. Molecular neurodegeneration Oh, H. n., Leventhal, O. n., Channappa, D. n., Henderson, V. W., Wyss-Coray, T. n., Lehallier, B. n., Gate, D. n. 2021; 16 (1): 3

  Abstract

  Cerebrospinal fluid (CSF) provides basic mechanical and immunological protection to the brain. Historically, analysis of CSF has focused on protein changes, yet recent studies have shed light on cellular alterations. Evidence now exists for involvement of intrathecal T cells in the pathobiology of neurodegenerative diseases. However, a standardized method for long-term preservation of CSF immune cells is lacking. Further, the functional role of CSF T cells and their cognate antigens in neurodegenerative diseases are largely unknown.We present a method for long-term cryopreservation of CSF immune cells for downstream single cell RNA and T cell receptor sequencing (scRNA-TCRseq) analysis. We observe preservation of CSF immune cells, consisting primarily of memory CD4+ and CD8+ T cells. We then utilize unbiased bioinformatics approaches to quantify and visualize TCR sequence similarity within and between disease groups. By this method, we identify clusters of disease-associated, antigen-specific TCRs from clonally expanded CSF T cells of patients with neurodegenerative diseases.Here, we provide a standardized approach for long-term storage of CSF immune cells. Additionally, we present unbiased bioinformatic approaches that will facilitate the discovery of target antigens of clonally expanded T cells in neurodegenerative diseases. These novel methods will help improve our understanding of adaptive immunity in the central nervous system.

  View details for DOI 10.1186/s13024-021-00423-w

  View details for PubMedID 33482851

• Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics. American journal of human genetics He, Z., Le Guen, Y., Liu, L., Lee, J., Ma, S., Yang, A. C., Liu, X., Rutledge, J., Losada, P. M., Song, B., Belloy, M. E., Butler, R. R., Longo, F. M., Tang, H., Mormino, E. C., Wyss-Coray, T., Greicius, M. D., Ionita-Laza, I. 2021

  Abstract

  Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

  View details for DOI 10.1016/j.ajhg.2021.10.009

  View details for PubMedID 34767756

• The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C. Science translational medicine Pluvinage, J. V., Sun, J., Claes, C., Flynn, R. A., Haney, M. S., Iram, T., Meng, X., Lindemann, R., Riley, N. M., Danhash, E., Chadarevian, J. P., Tapp, E., Gate, D., Kondapavulur, S., Cobos, I., Chetty, S., Pașca, A. M., Pașca, S. P., Berry-Kravis, E., Bertozzi, C. R., Blurton-Jones, M., Wyss-Coray, T. 2021; 13 (622): eabg2919

  Abstract

  [Figure: see text].

  View details for DOI 10.1126/scitranslmed.abg2919

  View details for PubMedID 34851695

• Asynchronous, contagious and digital aging. Nature aging Rando, T. A., Wyss-Coray, T. 2021; 1 (1): 29-35

  Abstract

  Aging has largely been defined by analog measures of organ and organismal dysfunction. This has led to the characterization of aging processes at the molecular and cellular levels that underlie these gradual changes. However, current knowledge does not fully explain the growing body of data emerging from large epidemiological, systems biology, and single cell studies of entire organisms pointing to varied rates of aging between individuals (different functionality and lifespan), across lifespan (asynchronous aging), and within an organism at the tissue and organ levels (aging mosaicism). Here we consider these inhomogeneities in the broader context of the rate of aging and from the perspective of underlying cellular changes. These changes reflect genetic, environmental, and stochastic factors that cells integrate to adopt new homeostatic, albeit less functional, states, such as cellular senescence. In this sense, cellular aging can be viewed, at least in part, as a quantal process we refer to as "digital aging". Nevertheless, analog declines of tissue dysfunction and organ failure with age could be the sum of underlying digital events. Importantly, cellular aging, digital or otherwise, is not uniform across time or space within the organism or between organisms of the same species. Certain tissues may exhibit earliest signs of cellular aging, acting as drivers for organismal aging as signals from those driver cells within those tissues may accelerate the aging of other cells locally or even systemically. Advanced methodologies at the systems level and at the single cell level are likely to continue to refine our understanding to the processes of how cells and tissues age and how the integration of those processes leads to the complexities of individual, organismal aging.

  View details for DOI 10.1038/s43587-020-00015-1

  View details for PubMedID 34223194

• CoolMPS for robust sequencing of single-nuclear RNAs captured by droplet-based method. Nucleic acids research Hahn, O., Fehlmann, T., Zhang, H., Munson, C. N., Vest, R. T., Borcherding, A., Liu, S., Villarosa, C., Drmanac, S., Drmanac, R., Keller, A., Wyss-Coray, T. 2020

  Abstract

  Massively-parallel single-cell and single-nucleus RNA sequencing (scRNA-seq, snRNA-seq) requires extensive sequencing to achieve proper per-cell coverage, making sequencing resources and availability of sequencers critical factors for conducting deep transcriptional profiling. CoolMPS is a novel sequencing-by-synthesis approach that relies on nucleotide labeling by re-usable antibodies, but whether it is applicable to snRNA-seq has not been tested. Here, we use a low-cost and off-the-shelf protocol to chemically convert libraries generated with the widely-used Chromium 10X technology to be sequenceable with CoolMPS technology. To assess the quality and performance of converted libraries sequenced with CoolMPS, we generated a snRNA-seq dataset from the hippocampus of young and old mice. Native libraries were sequenced on an Illumina Novaseq and libraries that were converted to be compatible with CoolMPS were sequenced on a DNBSEQ-400RS. CoolMPS-derived data faithfully replicated key characteristics of the native library dataset, including correct estimation of ambient RNA-contamination, detection of captured cells, cell clustering results, spatial marker gene expression, inter- and intra-replicate differences and gene expression changes during aging. In conclusion, our results show that CoolMPS provides a viable alternative to standard sequencing of RNA from droplet-based libraries.

  View details for DOI 10.1093/nar/gkaa1127

  View details for PubMedID 33264392

• Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age. Nature metabolism Brigger, D., Riether, C., van Brummelen, R., Mosher, K. I., Shiu, A., Ding, Z., Zbaren, N., Gasser, P., Guntern, P., Yousef, H., Castellano, J. M., Storni, F., Graff-Radford, N., Britschgi, M., Grandgirard, D., Hinterbrandner, M., Siegrist, M., Moullan, N., Hofstetter, W., Leib, S. L., Villiger, P. M., Auwerx, J., Villeda, S. A., Wyss-Coray, T., Noti, M., Eggel, A. 2020

  Abstract

  Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation. Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.

  View details for DOI 10.1038/s42255-020-0228-3

  View details for PubMedID 32694825

• Physiological blood-brain transport is impaired with age by a shift in transcytosis. Nature Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stahli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., Vest, R. T., Chaney, A., Lehallier, B., Olsson, N., du Bois, H., Hsieh, R., Cropper, H. C., Berdnik, D., Li, L., Wang, E. Y., Traber, G. M., Bertozzi, C. R., Luo, J., Snyder, M. P., Elias, J. E., Quake, S. R., James, M. L., Wyss-Coray, T. 2020

  Abstract

  The vascular interfaceof the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as isstandard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

  View details for DOI 10.1038/s41586-020-2453-z

  View details for PubMedID 32612231

• Influences of circulatory factors on intervertebral disc aging phenotype AGING-US Lei, C., Colangelo, D., Patil, P., Li, V., Ngo, K., Wang, D., Dong, Q., Yousefzadeh, M. J., Lin, H., Lee, J., Kang, J., Sowa, G., Wyss-Coray, T., Niedernhofer, L. J., Robbins, P. D., Huffman, D. M., Vo, N. 2020; 12 (12): 12285–304

  View details for Web of Science ID 000548154300013

• GeneTrail 3: advanced high-throughput enrichment analysis. Nucleic acids research Gerstner, N., Kehl, T., Lenhof, K., Muller, A., Mayer, C., Eckhart, L., Grammes, N. L., Diener, C., Hart, M., Hahn, O., Walter, J., Wyss-Coray, T., Meese, E., Keller, A., Lenhof, H. 2020

  Abstract

  We present GeneTrail3, a major extension of our web service GeneTrail that offers rich functionality for the identification, analysis, and visualization of deregulated biological processes. Our web service provides a comprehensive collection of biological processes and signaling pathways for 12 model organisms that can be analyzed with a powerful framework for enrichment and network analysis of transcriptomic, miRNomic, proteomic,and genomic data sets. Moreover, GeneTrail offers novel workflows for the analysis of epigenetic marks, time series experiments, and single cell data. We demonstrate the capabilities of our web service in two case-studies, which highlight that GeneTrail is well equipped for uncovering complex molecular mechanisms. GeneTrail is freely accessible at: http://genetrail.bioinf.uni-sb.de.

  View details for DOI 10.1093/nar/gkaa306

  View details for PubMedID 32379325

• Clonally expanded CD8 T cells patrol Alzheimer's cerebrospinal fluid Gate, D., Saligrama, N., Leventhal, O., Davis, M. M., Wyss-Coray, T. AMER ASSOC IMMUNOLOGISTS. 2020

  View details for Web of Science ID 000589972400098

• Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1 NATURE METABOLISM Brett, J. O., Arjona, M., Ikeda, M., Quarta, M., de Morree, A., Egner, I. M., Perandini, L. A., Ishak, H. D., Goshayeshi, A., Benjamin, D. I., Both, P., Rodriguez-Mateo, C., Betley, M. J., Wyss-Coray, T., Rando, T. A. 2020; 2 (4): 307-+

  View details for DOI 10.1038/s42255-020-0190-0

  View details for Web of Science ID 000536044100005

• Exercise rejuvenates quiescent skeletal muscle stem cells in old mice through restoration of Cyclin D1. Nature metabolism Brett, J. O., Arjona, M., Ikeda, M., Quarta, M., de Morrée, A., Egner, I. M., Perandini, L. A., Ishak, H. D., Goshayeshi, A., Benjamin, D. I., Both, P., Rodríguez-Mateo, C., Betley, M. J., Wyss-Coray, T., Rando, T. A. 2020; 2 (4): 307-317

  Abstract

  Aging impairs tissue repair. This is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young adult animals but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis. One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem cell function in the context of tissue regeneration are incompletely understood. Here we show that exercise in the form of voluntary wheel running accelerates muscle repair in old animals and improves old MuSC function. Through transcriptional profiling and genetic studies, we discovered that the restoration of old MuSC activation ability hinges on restoration of Cyclin D1, whose expression declines with age in MuSCs. Pharmacologic studies revealed that Cyclin D1 maintains MuSC activation capacity by repressing TGFβ signaling. Taken together, these studies demonstrate that voluntary exercise is a practicable intervention for old MuSC rejuvenation. Furthermore, this work highlights the distinct role of Cyclin D1 in stem cell quiescence.

  View details for DOI 10.1038/s42255-020-0190-0

  View details for PubMedID 32601609

  View details for PubMedCentralID PMC7323974

• Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues. Cell reports Chen, M. B., Yang, A. C., Yousef, H., Lee, D., Chen, W., Schaum, N., Lehallier, B., Quake, S. R., Wyss-Coray, T. 2020; 30 (13): 4418

  Abstract

  Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs-compared with arterial and venous BECs-undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.

  View details for DOI 10.1016/j.celrep.2020.03.012

  View details for PubMedID 32234477

• Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration (vol 21, pg 93, 2020) NATURE REVIEWS NEUROSCIENCE Pluvinage, J. V., Wyss-Coray, T. 2020

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41583-020-0293-3

  View details for Web of Science ID 000519420800001

  View details for PubMedID 32203300

• Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature neuroscience Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., Kim, J., Tevini, J., Felder, T. K., Wolinski, H., Bertozzi, C. R., Bassik, M. C., Aigner, L., Wyss-Coray, T. 2020

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41593-020-0595-9

  View details for PubMedID 32005940

• Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature neuroscience Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., Kim, J., Tevini, J., Felder, T. K., Wolinski, H., Bertozzi, C. R., Bassik, M. C., Aigner, L., Wyss-Coray, T. 2020

  Abstract

  Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call 'lipid-droplet-accumulating microglia' (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.

  View details for DOI 10.1038/s41593-019-0566-1

  View details for PubMedID 31959936

• Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., McBride, A., Pluvinage, J., Elahi, F., Tam, G. K., Kim, Y., Greicius, M., Wagner, A. D., Aigner, L., Galasko, D. R., Davis, M. M., Wyss-Coray, T. 2020

  Abstract

  Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

  View details for DOI 10.1038/s41586-019-1895-7

  View details for PubMedID 31915375

• Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging. Aging cell Lehallier, B. n., Shokhirev, M. N., Wyss-Coray, T. n., Johnson, A. A. 2020: e13256

  Abstract

  We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

  View details for DOI 10.1111/acel.13256

  View details for PubMedID 33031577

• Author Correction: Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nature neuroscience Marschallinger, J. n., Iram, T. n., Zardeneta, M. n., Lee, S. E., Lehallier, B. n., Haney, M. S., Pluvinage, J. V., Mathur, V. n., Hahn, O. n., Morgens, D. W., Kim, J. n., Tevini, J. n., Felder, T. K., Wolinski, H. n., Bertozzi, C. R., Bassik, M. C., Aigner, L. n., Wyss-Coray, T. n. 2020

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41593-020-0682-y

  View details for PubMedID 32719564

• Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age. Ageing research reviews Johnson, A. A., Shokhirev, M. N., Wyss-Coray, T. n., Lehallier, B. n. 2020: 101070

  Abstract

  The development of clinical interventions that significantly improve human healthspan requires robust markers of biological age as well as thoughtful therapeutic targets. To promote these goals, we performed a systematic review and analysis of human aging and proteomics studies. The systematic review includes 36 different proteomics analyses, each of which identified proteins that significantly changed with age. We discovered 1,128 proteins that had been reported by at least two or more analyses and 32 proteins that had been reported by five or more analyses. Each of these 32 proteins has known connections relevant to aging and age-related disease. GDF15, for example, extends both lifespan and healthspan when overexpressed in mice and is additionally required for the anti-diabetic drug metformin to exert beneficial effects on body weight and energy balance. Bioinformatic enrichment analyses of our 1,128 commonly identified proteins heavily implicated processes relevant to inflammation, the extracellular matrix, and gene regulation. We additionally propose a novel proteomic aging clock comprised of proteins that were reported to change with age in plasma in three or more different studies. Using a large patient cohort comprised of 3,301 subjects (aged 18-76 years), we demonstrate that this clock is able to accurately predict human age.

  View details for DOI 10.1016/j.arr.2020.101070

  View details for PubMedID 32311500

• Influences of circulatory factors on intervertebral disc aging phenotype. Aging Lei, C. n., Colangelo, D. n., Patil, P. n., Li, V. n., Ngo, K. n., Wang, D. n., Dong, Q. n., Yousefzadeh, M. J., Lin, H. n., Lee, J. n., Kang, J. n., Sowa, G. n., Wyss-Coray, T. n., Niedernhofer, L. J., Robbins, P. D., Huffman, D. M., Vo, N. n. 2020; 12

  Abstract

  Whether disc aging is influenced by factors beyond its local environment is an important unresolved question. Here we performed heterochronic parabiosis in mice to study the effects of circulating factors in young and old blood on age-associated intervertebral disc degeneration. Compared to young isochronic pairs (Y-Y), young mice paired with old mice (Y-O) showed significant increases in levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic tissue degeneration, but negligible changes in cellular senescence markers (p16INK4a, p21Cip1). Compared to old isochronic pairs (O-O), old mice paired with young mice (O-Y) exhibited a significant decrease in expression of cellular senescence markers (p16, p21, p53), but only marginal decreases in the levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic degeneration. Thus, exposing old mice to young blood circulation greatly suppressed disc cellular senescence, but only slightly decreased disc matrix imbalance and degeneration. Conversely, exposing young mice to old blood accelerated their disc matrix imbalance and tissue degeneration, with little effects on disc cellular senescence. Thus, non-cell autonomous effects of circulating factors on disc cellular senescence and matrix homeostasis are complex and suggest that disc matrix homeostasis is modulated by systemic factors and not solely through local disc cellular senescence.

  View details for DOI 10.18632/aging.103421

  View details for PubMedID 32527988

• Common diseases alter the physiological age-related blood microRNA profile. Nature communications Fehlmann, T., Lehallier, B., Schaum, N., Hahn, O., Kahraman, M., Li, Y., Grammes, N., Geffers, L., Backes, C., Balling, R., Kern, F., Kruger, R., Lammert, F., Ludwig, N., Meder, B., Fromm, B., Maetzler, W., Berg, D., Brockmann, K., Deuschle, C., von Thaler, A., Eschweiler, G. W., Milman, S., Barziliai, N., Reichert, M., Wyss-Coray, T., Meese, E., Keller, A. 2020; 11 (1): 5958

  Abstract

  Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5' mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers.

  View details for DOI 10.1038/s41467-020-19665-1

  View details for PubMedID 33235214

• Ageing hallmarks exhibit organ-specific temporal signatures. Nature Schaum, N. n., Lehallier, B. n., Hahn, O. n., Pálovics, R. n., Hosseinzadeh, S. n., Lee, S. E., Sit, R. n., Lee, D. P., Losada, P. M., Zardeneta, M. E., Fehlmann, T. n., Webber, J. T., McGeever, A. n., Calcuttawala, K. n., Zhang, H. n., Berdnik, D. n., Mathur, V. n., Tan, W. n., Zee, A. n., Tan, M. n., Pisco, A. O., Karkanias, J. n., Neff, N. F., Keller, A. n., Darmanis, S. n., Quake, S. R., Wyss-Coray, T. n. 2020

  Abstract

  Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

  View details for DOI 10.1038/s41586-020-2499-y

  View details for PubMedID 32669715

• A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 2020

  Abstract

  Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.

  View details for DOI 10.1038/s41586-020-2496-1

  View details for PubMedID 32669714

• Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration. Nature reviews. Neuroscience Pluvinage, J. V., Wyss-Coray, T. n. 2020

  Abstract

  A rapidly ageing population and a limited therapeutic toolbox urgently necessitate new approaches to treat neurodegenerative diseases. Brain ageing, the key risk factor for neurodegeneration, involves complex cellular and molecular processes that eventually result in cognitive decline. Although cell-intrinsic defects in neurons and glia may partially explain this decline, cell-extrinsic changes in the systemic environment, mediated by blood, have recently been shown to contribute to brain dysfunction with age. Here, we review the current understanding of how systemic factors mediate brain ageing, how these factors are regulated and how we can translate these findings into therapies for neurodegenerative diseases.

  View details for DOI 10.1038/s41583-019-0255-9

  View details for PubMedID 31913356

• A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mice models of Alzheimer's disease. Neuropharmacology Bellozi, P. M., Gomes, G. F., Machado da Silva, M. C., Vieira de Assis Lima, I., Batista, C. R., de Oliveira Carneiro Junior, W., Doria, J. G., Vieira, E. L., Vieira, R. P., de Freitas, R. P., Ferreira, C. N., Candelario-Jalil, E., Wyss-Coray, T., Ribeiro, F. M., de Oliveira, A. C. 2019: 107785

  Abstract

  Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-beta (Abeta) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Abeta induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Abeta injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Abeta accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB possess is protective against Abeta stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.

  View details for DOI 10.1016/j.neuropharm.2019.107785

  View details for PubMedID 31541651

• Targeting VCAM1 to reduce post-stroke neuroinflammation Zera, K., Peterson, T., Yousef, H., Lee, D., Wyss-Coray, T., Buckwalter, M. WILEY. 2019: 177

  View details for Web of Science ID 000478639800445

• An 80,000-Piece Puzzle of Alzheimer's Disease. Immunity Iram, T., Keller, A., Wyss-Coray, T. 2019; 50 (6): 1349–51

  Abstract

  To gain unfettered insight into one of the scourges of our aging societies, Mathys and colleagues in Nature (Mathys etal., 2019) illuminate the brain transcriptome of Alzheimer's disease at single-cell resolution. Their findings implicate oligodendrocytes, a cell type largely neglected in Alzheimer's disease research, and sex in the disease in intriguing ways.

  View details for DOI 10.1016/j.immuni.2019.05.016

  View details for PubMedID 31216459

• Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1 NATURE MEDICINE Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Koerbelin, J., Schwaninger, M., Buckwalter, M. S., Quake, S. R., Butcher, E. C., Wyss-Coray, T. 2019; 25 (6): 988-+

  View details for DOI 10.1038/s41591-019-0440-4

  View details for Web of Science ID 000470844400031

• CD22 blockade restores homeostatic microglial phagocytosis in ageing brains NATURE Pluvinage, J. V., Haney, M. S., Smith, B. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., Wyss-Coray, T. 2019; 568 (7751): 187-+

  View details for DOI 10.1038/s41586-019-1088-4

  View details for Web of Science ID 000464412700039

• CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature Pluvinage, J. V., Haney, M. S., Smith, B. A., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., Shuken, S. R., Gate, D., Scott, M., Khatri, P., Luo, J., Bertozzi, C. R., Bassik, M. C., Wyss-Coray, T. 2019

  Abstract

  Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNAsequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical Bcell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of alpha2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-beta oligomers and alpha-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

  View details for PubMedID 30944478

• Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy. Bioinformatics (Oxford, England) Ghaemi, M. S., DiGiulio, D. B., Contrepois, K., Callahan, B., Ngo, T. T., Lee-McMullen, B., Lehallier, B., Robaczewska, A., Mcilwain, D., Rosenberg-Hasson, Y., Wong, R. J., Quaintance, C., Culos, A., Stanley, N., Tanada, A., Tsai, A., Gaudilliere, D., Ganio, E., Han, X., Ando, K., McNeil, L., Tingle, M., Wise, P., Maric, I., Sirota, M., Wyss-Coray, T., Winn, V. D., Druzin, M. L., Gibbs, R., Darmstadt, G. L., Lewis, D. B., Partovi Nia, V., Agard, B., Tibshirani, R., Nolan, G., Snyder, M. P., Relman, D. A., Quake, S. R., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2019; 35 (1): 95–103

  Abstract

  Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary information: Supplementary data are available at Bioinformatics online.

  View details for PubMedID 30561547

• Undulating changes in human plasma proteome profiles across the lifespan. Nature medicine Lehallier, B. n., Gate, D. n., Schaum, N. n., Nanasi, T. n., Lee, S. E., Yousef, H. n., Moran Losada, P. n., Berdnik, D. n., Keller, A. n., Verghese, J. n., Sathyan, S. n., Franceschi, C. n., Milman, S. n., Barzilai, N. n., Wyss-Coray, T. n. 2019; 25 (12): 1843–50

  Abstract

  Aging is a predominant risk factor for several chronic diseases that limit healthspan1. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues2-10, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.

  View details for DOI 10.1038/s41591-019-0673-2

  View details for PubMedID 31806903

• Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nature medicine Yousef, H. n., Czupalla, C. J., Lee, D. n., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J. n., Berber, E. n., Lehallier, B. n., Mathur, V. n., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T. n., Hadeiba, H. n., Merkel, T. n., Körbelin, J. n., Schwaninger, M. n., Buckwalter, M. S., Quake, S. R., Butcher, E. C., Wyss-Coray, T. n. 2019

  Abstract

  An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.

  View details for PubMedID 31086348

• Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature Dulken, B. W., Buckley, M. T., Navarro Negredo, P. n., Saligrama, N. n., Cayrol, R. n., Leeman, D. S., George, B. M., Boutet, S. C., Hebestreit, K. n., Pluvinage, J. V., Wyss-Coray, T. n., Weissman, I. L., Vogel, H. n., Davis, M. M., Brunet, A. n. 2019

  Abstract

  The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.

  View details for DOI 10.1038/s41586-019-1362-5

  View details for PubMedID 31270459

• Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy BIOINFORMATICS Ghaemi, M., DiGiulio, D. B., Contrepois, K., Callahan, B., Ngo, T. M., Lee-McMullen, B., Lehallier, B., Robaczewska, A., Mcilwain, D., Rosenberg-Hasson, Y., Wong, R. J., Quaintance, C., Culos, A., Stanley, N., Tanada, A., Tsai, A., Gaudilliere, D., Ganio, E., Han, X., Ando, K., McNeil, L., Tingle, M., Wise, P., Maric, I., Sirota, M., Wyss-Coray, T., Winn, V. D., Druzin, M. L., Gibbs, R., Darmstadt, G. L., Lewis, D. B., Nia, V., Agard, B., Tibshirani, R., Nolan, G., Snyder, M. P., Relman, D. A., Quake, S. R., Shaw, G. M., Stevenson, D. K., Angst, M. S., Gaudilliere, B., Aghaeepour, N. 2019; 35 (1): 95–103

  View details for DOI 10.1093/bioinformatics/bty537

  View details for Web of Science ID 000459313900012

• Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration. Molecular neurodegeneration Bieri, G., Lucin, K. M., O'Brien, C. E., Zhang, H., Villeda, S. A., Wyss-Coray, T. 2018; 13 (1): 68

  Abstract

  BACKGROUND: Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer's disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo.METHODS: Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus.RESULTS: We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo.CONCLUSIONS: Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration.

  View details for PubMedID 30594228

• Collagenase-based Single Cell Isolation of Primary Murine Brain Endothelial Cells Using Flow Cytometry. Bio-protocol Czupalla, C. J., Yousef, H., Wyss-Coray, T., Butcher, E. C. 2018; 8 (22)

  Abstract

  The brain endothelium is a highly specialized vascular structure that maintains the activity and integrity of the central nervous system (CNS). Previous studies have reported that the integrity of the brain endothelium is compromised in a plethora of neuropathologies. Therefore, it is of particular interest to establish a method that enables researchers to investigate and understand the molecular changes in CNS endothelial cells and underlying mechanisms in conjunction with murine models of disease. In the past, approaches to isolate endothelial cells have either involved the use of transgenic reporter mice or suffered from insufficiently pure cell populations and poor yield. This protocol here is based on well-established protocols that were modified and combined to allow single cell isolation of highly pure brain endothelial cell populations using fluorescence activated cell sorting (FACS). Briefly, after careful removal of the meninges and dissection of the cortex/hippocampus, the brain tissue is mechanically homogenized and enzymatically digested in two steps resulting in a single cell suspension. Cells are stained with a cocktail of fluorochrome-conjugated antibodies identifying not only brain endothelial cells, but also potentially contaminating cell types such as pericytes, astrocytes, and lineage cells. Using flow cytometry, cell populations are separated and sorted directly into either RNA lysis buffer for bulk RNA analyses (e.g., RNA microarray and RNA-Seq) or in pure fetal bovine serum to preserve viability for other downstream applications such as single cell RNA-Seq and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-Seq). The protocol does not require the expression of a transgene to label brain endothelial cells and thus, may be applied to any mouse model. In our hands, the protocol has been highly reproducible with an average yield of 3 * 105 cells from a pool of four adult mice.

  View details for PubMedID 30637296

• Papain-based Single Cell Isolation of Primary Murine Brain Endothelial Cells Using Flow Cytometry. Bio-protocol Yousef, H., Czupalla, C. J., Lee, D., Butcher, E. C., Wyss-Coray, T. 2018; 8 (22)

  Abstract

  Brain endothelial cells (BECs) form the integral component of the blood-brain barrier (BBB) which separates the systemic milieu from the brain parenchyma and protects the brain from pathogens and circulating factors. In order to study BEC biology, it was of particular interest to establish a method that enables researchers to investigate and understand the underlying molecular mechanisms regulating their function during homeostasis, aging and disease. Furthermore, due to the heterogeneity of the cerebrovasculature and different vessel types that comprise the BBB, it is of particular interest to isolate primary BECs for single cell analysis from various subregions of the brain, such as the neurogenic and highly vascularized hippocampus and to enrich for specific vessel types. In the past, approaches to isolate endothelial cells were dependent on transgenic mice and often resulted in insufficiently pure cell populations and poor yield. This protocol describes a technique that allows single-cell isolation of highly pure brain endothelial cell populations using fluorescence activated cell sorting (FACS). Briefly, after perfusion and careful removal of the meninges, and dissection of the cortex/hippocampus, the brain tissue is mechanically homogenized and enzymatically digested resulting in a single cell suspension. Cells are stained with fluorochrome-conjugated antibodies identifying CD31+ brain endothelial cells, as well as CD45+CD11b+ myeloid cells for exclusion. Using flow cytometry, cell populations are separated and CD31+BECs are sorted in bulk into RNA later or as single cells directly into either RNA lysis buffer for single or bulk RNA-Seq analyses. The protocol does not require the expression of a transgene to label brain endothelial cells and thus, may be applied to any mouse model. In our hands, the protocol has been highly reproducible with an average yield of 1 × 105 cells isolated from an adult mouse cortex/hippocampus.

  View details for DOI 10.21769/BioProtoc.3091

  View details for PubMedID 31032379

  View details for PubMedCentralID PMC6482965

• Papain-based Single Cell Isolation of Primary Murine Brain Endothelial Cells Using Flow Cytometry BIO-PROTOCOL Yousef, H., Czupalla, C. J., Lee, D., Butcher, E. C., Wyss-Coray, T. 2018; 8 (22)

  View details for DOI 10.21769/BioProtoc.3091

  View details for Web of Science ID 000458027400011

• Nociceptive and Cognitive Changes in a Murine Model of Polytrauma. The journal of pain : official journal of the American Pain Society Sahbaie, P., Tajerian, M., Yang, P., Irvine, K. A., Huang, T., Luo, J., Wyss-Coray, T., Clark, J. D. 2018

  Abstract

  POLYTRAUMA COMMONLY INVOLVES CONCUSSION (MILD TRAUMATIC BRAIN INJURY: mTBI) and peripheral trauma including limb fractures. Interactions between mTBI and peripheral injuries are poorly understood, both leading to chronic pain and neurobehavioral impairments. To elucidate these interactions, a murine polytrauma model was developed. mTBI alone resulted in similar increased mechanical allodynia in males and females. Female fracture and polytrauma groups displayed greater increases in hindpaw tactile hypersensitivity for weeks after injury than respective male groups. Capsaicin evoked spontaneous pain behaviors were greater in fracture and polytrauma females compared to males. The mTBI and polytrauma males displayed significant deficits in spatial working memory. All fracture, mTBI or polytrauma groups had deficits in object recognition memory. Only male mTBI or polytrauma mice showed greater agitation and increased risk taking behavior in open field testing as well as zero maze tests. Additionally, impaired diffuse noxious inhibitory control was observed in all mTBI and polytrauma mice. The model presented offers clinically relevant features useful for studying persistent pain, cognitive and other behavioral changes after TBI including polytrauma. A better understanding of nervous system dysfunction after TBI and polytrauma might help prevent or reduce persistent pain and disability in these patients.PERSPECTIVE: The polytrauma model presented has relevant features of chronic pain and neurobehavioral impairments useful for studying mechanisms involved in their development. This model may have special value in understanding altered descending pain modulation after TBI and polytrauma.

  View details for PubMedID 29964216

• Multiple Click-Selective tRNA Synthetases Expand Mammalian Cell-Specific Proteomics JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Yang, A. C., Du Bois, H., Olsson, N., Gate, D., Lehallier, B., Berdnik, D., Brewer, K. D., Bertozzi, C. R., Elias, J. E., Wyss-Coray, T. 2018; 140 (23): 7046–51

  Abstract

  Bioorthogonal tools enable cell-type-specific proteomics, a prerequisite to understanding biological processes in multicellular organisms. Here we report two engineered aminoacyl-tRNA synthetases for mammalian bioorthogonal labeling: a tyrosyl ( ScTyrY43G) and a phenylalanyl ( MmPheT413G) tRNA synthetase that incorporate azide-bearing noncanonical amino acids specifically into the nascent proteomes of host cells. Azide-labeled proteins are chemoselectively tagged via azide-alkyne cycloadditions with fluorophores for imaging or affinity resins for mass spectrometric characterization. Both mutant synthetases label human, hamster, and mouse cell line proteins and selectively activate their azido-bearing amino acids over 10-fold above the canonical. ScTyrY43G and MmPheT413G label overlapping but distinct proteomes in human cell lines, with broader proteome coverage upon their coexpression. In mice, ScTyrY43G and MmPheT413G label the melanoma tumor proteome and plasma secretome. This work furnishes new tools for mammalian residue-specific bioorthogonal chemistry, and enables more robust and comprehensive cell-type-specific proteomics in live mammals.

  View details for DOI 10.1021/jacs.8b03074

  View details for Web of Science ID 000435525500001

  View details for PubMedID 29775058

• [F-18] FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis JOURNAL OF NEUROINFLAMMATION Hoehne, A., James, M. L., Alam, I. S., Ronald, J. A., Schneider, B., D'Souza, A., Witney, T. H., Andrews, L. E., Cropper, H. C., Behera, D., Gowrishankar, G., Ding, Z., Wyss-Coray, T., Chin, F. T., Biswal, S., Gambhir, S. S. 2018; 15

  View details for DOI 10.1186/s12974-018-1080-1

  View details for Web of Science ID 000425975200001

• [18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis. Journal of neuroinflammation Hoehne, A., James, M. L., Alam, I. S., Ronald, J. A., Schneider, B., D'Souza, A., Witney, T. H., Andrews, L. E., Cropper, H. C., Behera, D., Gowrishankar, G., Ding, Z., Wyss-Coray, T., Chin, F. T., Biswal, S., Gambhir, S. S. 2018; 15 (1): 55

  Abstract

  The cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS.Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55) peptide in complete Freund's adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro.[18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal.These data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation.

  View details for DOI 10.1186/s12974-018-1080-1

  View details for PubMedID 29471880

  View details for PubMedCentralID PMC5822551

• Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA neurology Sha, S. J., Deutsch, G. K., Tian, L. n., Richardson, K. n., Coburn, M. n., Gaudioso, J. L., Marcal, T. n., Solomon, E. n., Boumis, A. n., Bet, A. n., Mennes, M. n., van Oort, E. n., Beckmann, C. F., Braithwaite, S. P., Jackson, S. n., Nikolich, K. n., Stephens, D. n., Kerchner, G. A., Wyss-Coray, T. n. 2018

  Abstract

  Young mouse plasma restores memory in aged mice, but, to our knowledge, the effects are unknown in patients with Alzheimer disease (AD).To assess the safety, tolerability, and feasibility of infusions of young fresh frozen plasma (yFFP) from donors age 18 to 30 years in patients with AD.The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. Patients and informants were masked to treatment and subjective measurements. After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked. Patients were enrolled solely at Stanford University, a tertiary academic medical center, from September 2014 to December 2016, when enrollment reached its target. Eighteen consecutive patients with probable mild to moderate AD dementia, a Mini-Mental State Examination (score of 12 to 24 inclusive), and an age of 50 to 90 years were enrolled. Thirty-one patients were screened and 13 were excluded: 11 failed the inclusion criteria and 2 declined to participate.One unit of yFFP from male donors/placebo infused once weekly for 4 weeks.The primary outcomes were the safety, tolerability, and feasibility of 4 weekly yFFP infusions. Safety end point analyses included all patients who received the study drug/placebo.There was no difference in the age (mean [SD], 74.17 [7.96] years), sex (12 women [67%]), or baseline Mini-Mental State Examination score (mean [SD], 19.39 [3.24]) between the crossover (n = 9) and open-label groups (n = 9). There were no related serious adverse events. One patient discontinued participation because of urticaria and another because of an unrelated stroke. There was no statistically significant difference between the plasma (17 [94.4%]) and placebo (9 [100.0%]) cohorts for other adverse events, which were mild to moderate in severity. The most common adverse events in the plasma group included hypertension (3 [16.7%]), dizziness (2 [11.1%]), sinus bradycardia (3 [16.7%]), headache (3 [16.7%]), and sinus tachycardia (3 [16.7%]). The mean visit adherence (n = 18) was 86% (interquartile range, 87%-100%) and adherence, accounting for a reduction in the total visit requirement due to early patient discontinuation, was 96% (interquartile range, 89%-100%).The yFFP treatment was safe, well tolerated, and feasible. The study's limitations were the small sample size, short duration, and change in study design. The results warrant further exploration in larger, double-blinded placebo-controlled clinical trials.ClinicalTrials.gov Identifier: NCT02256306.

  View details for PubMedID 30383097

• Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron Li, Q. n., Cheng, Z. n., Zhou, L. n., Darmanis, S. n., Neff, N. F., Okamoto, J. n., Gulati, G. n., Bennett, M. L., Sun, L. O., Clarke, L. E., Marschallinger, J. n., Yu, G. n., Quake, S. R., Wyss-Coray, T. n., Barres, B. A. 2018

  Abstract

  Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region. By contrast, early postnatal microglia are more heterogeneous. We discovered a proliferative-region-associated microglia (PAM) subset, mainly found in developing white matter, that shares a characteristic gene signature with degenerative disease-associated microglia (DAM). Such PAM have amoeboid morphology, are metabolically active, and phagocytose newly formed oligodendrocytes. This scRNA-seq atlas will be a valuable resource for dissecting innate immune functions in health and disease.

  View details for PubMedID 30606613

• Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018; 562 (7727): 367–72

  Abstract

  Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

  View details for DOI 10.1038/s41586-018-0590-4

  View details for PubMedID 30283141

• Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation NEURON Mathur, V., Burai, R., Vest, R. T., Bonanno, L. N., Lehallier, B., Zardeneta, M. E., Mistry, K. N., Do, D., Marsh, S. E., Abud, E. M., Blurton-Jones, M., Li, L., Lashuel, H. A., Wyss-Coray, T. 2017; 96 (6): 1290-+

  Abstract

  Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNβ, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.

  View details for PubMedID 29268096

  View details for PubMedCentralID PMC5806703

• Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control JOURNAL OF VIROLOGY Ruiz-Riol, M., Berdnik, D., Llano, A., Mothe, B., Galvez, C., Perez-Alvarez, S., Oriol-Tordera, B., Olvera, A., Silva-Arrieta, S., Meulbroek, M., Pujol, F., Coll, J., Martinez-Picado, J., Ganoza, C., Sanchez, J., Gomez, G., Wyss-Coray, T., Brander, C. 2017; 91 (16)

  Abstract

  Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/β-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach ("communicome") has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda.

  View details for PubMedID 28592538

  View details for PubMedCentralID PMC5533920

• OH MYeloid! Immune cells wreaking havoc on brain homeostasis. The EMBO journal Bonanno, L., Wyss-Coray, T. 2017; 36 (13): 1803-1805

  View details for DOI 10.15252/embj.201797465

  View details for PubMedID 28623242

  View details for PubMedCentralID PMC5494462

• Human umbilical cord plasma proteins revitalize hippocampal function in aged mice NATURE Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., Hinkson, I. V., Angst, M. S., Wyss-Coray, T. 2017; 544 (7651): 488-?

  Abstract

  Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

  View details for DOI 10.1038/nature22067

  View details for PubMedID 28424512

• Deficiency in Neuronal TGF-beta Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-beta Signaling Protects against MPTP Neurotoxicity in Mice JOURNAL OF NEUROSCIENCE Tesseur, I., Nguyen, A., Chang, B., Li, L., Woodling, N. S., Wyss-Coray, T., Luo, J. 2017; 37 (17): 4584-4592

  Abstract

  Transforming growth factor-β (TGF-β) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-β signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-β signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-β signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-β signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-β (TGF-β) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-β signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-β signaling as a potential therapy for Parkinson's disease.

  View details for DOI 10.1523/JNEUROSCI.2952-16.2017

  View details for Web of Science ID 000401038400014

  View details for PubMedID 28363982

• Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhang, Z., Takeda-Uchimura, Y., Foyez, T., Ohtake-Niimi, S., Narentuya, Akatsu, H., Nishitsuji, K., Michikawa, M., Wyss-Coray, T., Kadomatsu, K., Uchimura, K. 2017; 114 (14): E2947-E2954

  Abstract

  We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1(-/-)) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1(-/-) primary microglia showed an increased level of amyloid-β phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1(-/-) mice manifested reduced cerebral amyloid-β deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.

  View details for DOI 10.1073/pnas.1615036114

  View details for Web of Science ID 000398159000019

  View details for PubMedID 28320965

• Microglial complement receptor 3 regulates brain A beta levels through secreted proteolytic activity JOURNAL OF EXPERIMENTAL MEDICINE Czirr, E., Castello, N. A., Mosher, K. I., Castellano, J. M., Hinkson, I. V., Lucin, K. M., Baeza-Raja, B., Ryu, J. K., Li, L., Farina, S. N., Belichenko, N. P., Longo, F. M., Akassoglou, K., Britschgi, M., Cirrito, J. R., Wyss-Coray, T. 2017; 214 (4): 1081-1092

  Abstract

  Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble β-amyloid (Aβ) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aβ accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aβ by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aβ levels and Aβ half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aβ clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aβ metabolism and defining a potential new therapeutic target in AD.

  View details for DOI 10.1084/jem.20162011

  View details for Web of Science ID 000398051100015

  View details for PubMedID 28298456

• Microglial Barriers to Viral Gene Delivery. Neuron Pluvinage, J. V., Wyss-Coray, T. 2017; 93 (3): 468-470

  Abstract

  In this issue of Neuron, Tufail et al. present an underlying mechanism for microglia-mediated elimination of virally transduced cells in the central nervous system. These findings could contribute to the development of improved gene therapies for various neurological disorders by exploring why microglia destroy viable cells following viral infection.

  View details for DOI 10.1016/j.neuron.2017.01.025

  View details for PubMedID 28182900

• Ageing, neurodegeneration and brain rejuvenation NATURE Wyss-Coray, T. 2016; 539 (7628): 180-186

  Abstract

  Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.

  View details for DOI 10.1038/nature20411

  View details for Web of Science ID 000387318500028

  View details for PubMedID 27830812

  View details for PubMedCentralID PMC5172605

• Preclinical Assessment of Young Blood Plasma for Alzheimer Disease JAMA NEUROLOGY Middeldorp, J., Lehallier, B., Villeda, S. A., Miedema, S. S., Evans, E., Czirr, E., Zhang, H., Luo, J., Stan, T., Mosher, K. I., Masliah, E., Wyss-Coray, T. 2016; 73 (11): 1325-1333

  Abstract

  Alzheimer disease (AD) pathology starts long before clinical symptoms manifest, and there is no therapy to treat, delay, or prevent the disease. A shared blood circulation between 2 mice (aka parabiosis) or repeated injections of young blood plasma (plasma from 2- to 3-month-old mice) into old mice has revealed benefits of young plasma on synaptic function and behavior. However, to our knowledge, the potential benefit of young blood has not been tested in preclinical models of neurodegeneration or AD.To determine whether young blood plasma ameliorates pathology and cognition in a mouse model for AD and could be a possible future treatment for the disease.In this preclinical study, mice that harbor a human mutant APP gene, which causes familial AD, were aged to develop AD-like disease including accumulation of amyloid plaques, loss of synaptic and neuronal proteins, and behavioral deficits. The initial parabiosis studies were done in 2010, and the final studies were conducted in 2014. Alzheimer disease model mice were then treated either by surgically connecting them with a young healthy mouse, thus providing a shared blood circulation through parabiosis, or through repeated injections of plasma from young mice.Neuropathological parameters and changes in hippocampal gene expression in response to the treatment were assessed. In addition, cognition was tested in AD model mice intravenously injected with young blood plasma.Aged mutant amyloid precursor protein mice with established disease showed a near complete restoration in levels of synaptic and neuronal proteins after exposure to young blood in parabiosis (synaptophysin P = .02; calbindin P = .02) or following intravenous plasma administration (synaptophysin P < .001; calbindin P = .14). Amyloid plaques were not affected, but the beneficial effects in neurons in the hippocampus were accompanied by a reversal of abnormal extracellular receptor kinase signaling (P = .05), a kinase implicated in AD. Moreover, young plasma administration was associated with improved working memory (P = .01) and associative memory (P = .02) in amyloid precursor protein mice.Factors in young blood have the potential to ameliorate disease in a model of AD.

  View details for DOI 10.1001/jamaneurol.2016.3185

  View details for Web of Science ID 000388578600013

  View details for PubMedID 27598869

  View details for PubMedCentralID PMC5172595

• Traumatic Brain Injury Imaging in the Second Near-Infrared Window with a Molecular Fluorophore. Advanced materials Zhang, X., Wang, H., Antaris, A. L., Li, L., Diao, S., Ma, R., Nguyen, A., Hong, G., Ma, Z., Wang, J., Zhu, S., Castellano, J. M., Wyss-Coray, T., Liang, Y., Luo, J., Dai, H. 2016; 28 (32): 6872-6879

  Abstract

  Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. A bright, renal-excreted, and biocompatible near-infrared II fluorophore for in vivo imaging of TBI is designed. A transient hypoperfusion in the injured cerebral region, followed by fluorophore leakage, is observed. NIR-II fluorophores can provide noninvasive assessment of TBI.

  View details for DOI 10.1002/adma.201600706

  View details for PubMedID 27253071

• In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model SCIENTIFIC REPORTS Castellano, J. M., Palner, M., Li, S., Freeman, G. M., Andy Nguyen, A., Shen, B., Stan, T., Mosher, K. I., Chin, F. T., de Lecea, L., Luo, J., Wyss-Coray, T. 2016; 6

  Abstract

  The sharing of circulation between two animals using a surgical procedure known as parabiosis has created a wealth of information towards our understanding of physiology, most recently in the neuroscience arena. The systemic milieu is a complex reservoir of tissues, immune cells, and circulating molecules that is surprisingly not well understood in terms of its communication across organ systems. While the model has been used to probe complex physiological questions for many years, critical parameters of recovery and exchange kinetics remain incompletely characterized, limiting the ability to design experiments and interpret results for complex questions. Here we provide evidence that mice joined by parabiosis gradually recover much physiology relevant to the study of brain function. Specifically, we describe the timecourse for a variety of recovery parameters, including those for general health and metabolism, motor coordination, activity, and sleep behavior. Finally, we describe the kinetics of chimerism for several lymphocyte populations as well as the uptake of small molecules into the brains of mice following parabiosis. Our characterization provides an important resource to those attempting to understand the complex interplay between the immune system and the brain as well as other organ systems.

  View details for DOI 10.1038/srep29015

  View details for Web of Science ID 000378851500002

  View details for PubMedID 27364522

  View details for PubMedCentralID PMC4929497

• Erratum to: Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain. Molecular neurodegeneration Jaeger, P. A., Lucin, K. M., Britschgi, M., Vardarajan, B., Huang, R. P., Kirby, E. D., Abbey, R., Boeve, B. F., Boxer, A. L., Farrer, L. A., Finch, N., Graff-Radford, N. R., Head, E., Hofree, M., Huang, R., Johns, H., Karydas, A., Knopman, D. S., Loboda, A., Masliah, E., Narasimhan, R., Petersen, R. C., Podtelezhnikov, A., Pradhan, S., Rademakers, R., Sun, C. H., Younkin, S. G., Miller, B. L., Ideker, T., Wyss-Coray, T. 2016; 11 (1): 42

  View details for DOI 10.1186/s13024-016-0105-4

  View details for PubMedID 27216421

  View details for PubMedCentralID PMC4877764

• Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain MOLECULAR NEURODEGENERATION Jaeger, P. A., Lucin, K. M., Britschgi, M., Vardarajan, B., Huang, R., Kirby, E. D., Abbey, R., Boeve, B. F., Boxer, A. L., Farrer, L. A., Finch, N., Graff-Radford, N. R., Head, E., Hoffree, M., Huang, R., Johns, H., Karydas, A., Knopman, D. S., Loboda, A., Masliah, E., Narasimhan, R., Petersen, R. C., Podtelezhnikov, A., Pradhan, S., Rademakers, R., Sun, C., Younkin, S. G., Miller, B. L., Ideker, T., Wyss-Coray, T. 2016; 11

  Abstract

  Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.To access this information we probed relative levels of close to 600 secreted signaling proteins from patients' blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer's disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.

  View details for DOI 10.1186/s13024-016-0095-2

  View details for Web of Science ID 000374728400001

  View details for PubMedID 27112350

  View details for PubMedCentralID PMC4845325

• Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease JAMA NEUROLOGY Lehallier, B., Essioux, L., Gayan, J., Alexandridis, R., Nikolcheva, T., Wyss-Coray, T., Britschgi, M. 2016; 73 (2): 203-212

  Abstract

  A reliable method of detecting Alzheimer disease (AD) in its prodromal state is needed for patient stratification in clinical trials or for personalizing existing or potential upcoming therapies. Current cerebrospinal fluid (CSF)- or imaging-based single biomarkers for AD offer reliable identification of patients with underlying AD but insufficient prediction of the rate of AD progression.To optimize prediction of progression from mild cognitive impairment (MCI) to AD dementia by combining information from diverse patient variables.This cohort study from the Alzheimer Disease Neuroimaging Initiative (ADNI) enrolled 928 patients with MCI at baseline and 249 selected variables available in the ADNI data set. Variables included clinical and demographic data, cognitive scores, magnetic resonance imaging-based brain volumetric data, the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes, and analyte levels measured in the CSF and plasma. Data were collected in July 2012 and analyzed from July 1, 2012, to June 1, 2015.Progression from MCI to AD within 1 to 6 years. To determine whether combinations of markers could predict progression from MCI to AD within 1 to 6 years, the elastic net algorithm was used in an iterative resampling of a training- and test-based variable selection and modeling approach.Among the 928 patients with MCI in the ADNI database, 94 had 224 of the required variables available for the modeling. The results showed the contributions of age, Clinical Dementia Rating Sum of Boxes composite test score, hippocampal volume, and multiple plasma and CSF factors in modeling progression to AD. A combination of apolipoprotein A-II and cortisol levels in plasma and fibroblast growth factor 4, heart-type fatty acid binding protein, calcitonin, and tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) in CSF allowed for reliable prediction of disease status 3 years from the time of sample collection (80% classification accuracy, 88% sensitivity, and 70% specificity).These study findings suggest that a combination of markers measured in plasma and CSF, distinct from β-amyloid and tau, could prove useful in predicting midterm progression from MCI to AD dementia. Such a large-scale, multivariable-based analytical approach could be applied to other similar large data sets involving AD and beyond.

  View details for DOI 10.1001/jamaneurol.2015.3135

  View details for Web of Science ID 000385845500012

  View details for PubMedCentralID PMC5214993

• Beclin 1 regulates neuronal transforming growth factor-beta signaling by mediating recycling of the type I receptor ALK5 MOLECULAR NEURODEGENERATION O'Brien, C. E., Bonanno, L., Zhang, H., Wyss-Coray, T. 2015; 10

  View details for DOI 10.1186/s13024-015-0065-0

  View details for Web of Science ID 000366822900002

  View details for PubMedID 26692002

• Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease. JAMA neurology Lehallier, B., Essioux, L., Gayan, J., Alexandridis, R., Nikolcheva, T., Wyss-Coray, T., Britschgi, M. 2015: 1-10

  Abstract

  A reliable method of detecting Alzheimer disease (AD) in its prodromal state is needed for patient stratification in clinical trials or for personalizing existing or potential upcoming therapies. Current cerebrospinal fluid (CSF)- or imaging-based single biomarkers for AD offer reliable identification of patients with underlying AD but insufficient prediction of the rate of AD progression.To optimize prediction of progression from mild cognitive impairment (MCI) to AD dementia by combining information from diverse patient variables.This cohort study from the Alzheimer Disease Neuroimaging Initiative (ADNI) enrolled 928 patients with MCI at baseline and 249 selected variables available in the ADNI data set. Variables included clinical and demographic data, cognitive scores, magnetic resonance imaging-based brain volumetric data, the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes, and analyte levels measured in the CSF and plasma. Data were collected in July 2012 and analyzed from July 1, 2012, to June 1, 2015.Progression from MCI to AD within 1 to 6 years. To determine whether combinations of markers could predict progression from MCI to AD within 1 to 6 years, the elastic net algorithm was used in an iterative resampling of a training- and test-based variable selection and modeling approach.Among the 928 patients with MCI in the ADNI database, 94 had 224 of the required variables available for the modeling. The results showed the contributions of age, Clinical Dementia Rating Sum of Boxes composite test score, hippocampal volume, and multiple plasma and CSF factors in modeling progression to AD. A combination of apolipoprotein A-II and cortisol levels in plasma and fibroblast growth factor 4, heart-type fatty acid binding protein, calcitonin, and tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) in CSF allowed for reliable prediction of disease status 3 years from the time of sample collection (80% classification accuracy, 88% sensitivity, and 70% specificity).These study findings suggest that a combination of markers measured in plasma and CSF, distinct from β-amyloid and tau, could prove useful in predicting midterm progression from MCI to AD dementia. Such a large-scale, multivariable-based analytical approach could be applied to other similar large data sets involving AD and beyond.

  View details for DOI 10.1001/jamaneurol.2015.3135

  View details for PubMedID 26659895

• The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging COLD SPRING HARBOR PERSPECTIVES IN MEDICINE DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)

  Abstract

  Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis.

  View details for DOI 10.1101/cshperspect.a025874

  View details for Web of Science ID 000368599500002

• Impact of peripheral myeloid cells on amyloid-ß pathology in Alzheimer's disease-like mice. journal of experimental medicine Prokop, S., Miller, K. R., Drost, N., Handrick, S., Mathur, V., Luo, J., Wegner, A., Wyss-Coray, T., Heppner, F. L. 2015; 212 (11): 1811-1818

  Abstract

  Although central nervous system-resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer's disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell-based therapies for AD.

  View details for DOI 10.1084/jem.20150479

  View details for PubMedID 26458768

  View details for PubMedCentralID PMC4612091

• Blood-Borne Revitalization of the Aged Brain JAMA NEUROLOGY Castellano, J. M., Kirby, E. D., Wyss-Coray, T. 2015; 72 (10): 1191-1194

  Abstract

  In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain. Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors. The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.

  View details for DOI 10.1001/jamaneurol.2015.1616

  View details for Web of Science ID 000362963000016

  View details for PubMedID 26237737

• Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-beta signaling and astrocyte functions NATURE NEUROSCIENCE Schachtrup, C., Ryu, J. K., Mammadzada, K., Khan, A. S., Carlton, P. M., Perez, A., Christian, F., Le Moan, N., Vagena, E., Baeza-Raja, B., Rafalski, V., Chan, J. P., Nitschke, R., Houslay, M. D., Ellisman, M. H., Wyss-Coray, T., Palop, J. J., Akassoglou, K. 2015; 18 (8): 1077-?

  Abstract

  Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.

  View details for DOI 10.1038/nn.4054

  View details for Web of Science ID 000358605400006

• beta 2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis NATURE MEDICINE Smith, L. K., He, Y., Park, J., Bieri, G., Snethlage, C. E., Lin, K., Gontier, G., Wabl, R., Plambeck, K. E., Udeochu, J., Wheatley, E. G., Bouchard, J., Eggel, A., Narasimha, R., Grant, J. L., Luo, J., Wyss-Coray, T., Villeda, S. A. 2015; 21 (8): 932-937

  Abstract

  Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

  View details for DOI 10.1038/nm.3898

  View details for Web of Science ID 000359181000021

  View details for PubMedID 26147761

  View details for PubMedCentralID PMC4529371

• Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-ß signaling and astrocyte functions. Nature neuroscience Schachtrup, C., Ryu, J. K., Mammadzada, K., Khan, A. S., Carlton, P. M., Perez, A., Christian, F., Le Moan, N., Vagena, E., Baeza-Raja, B., Rafalski, V., Chan, J. P., Nitschke, R., Houslay, M. D., Ellisman, M. H., Wyss-Coray, T., Palop, J. J., Akassoglou, K. 2015; 18 (8): 1077-1080

  Abstract

  Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors.

  View details for DOI 10.1038/nn.4054

  View details for PubMedID 26120963

• Go with your gut: microbiota meet microglia. Nature neuroscience Mosher, K. I., Wyss-Coray, T. 2015; 18 (7): 930-931

  View details for DOI 10.1038/nn.4051

  View details for PubMedID 26108718

• CalFluors: A Universal Motif for Fluorogenic Azide Probes across the Visible Spectrum JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Shieh, P., Dien, V. T., Beahm, B. J., Castellano, J. M., Wyss-Coray, T., Bertozzi, C. R. 2015; 137 (22): 7145-7151

  Abstract

  Fluorescent bioorthogonal smart probes across the visible spectrum will enable sensitive visualization of metabolically labeled molecules in biological systems. Here we present a unified design, based on the principle of photoinduced electron transfer, to access a panel of highly fluorogenic azide probes that are activated by conversion to the corresponding triazoles via click chemistry. Termed the CalFluors, these probes possess emission maxima that range from green to far red wavelengths, and enable sensitive biomolecule detection under no-wash conditions. We used the CalFluor probes to image various alkyne-labeled biomolecules (glycans, DNA, RNA, and proteins) in cells, developing zebrafish, and mouse brain tissue slices.

  View details for DOI 10.1021/jacs.5b02383

  View details for Web of Science ID 000356322300038

  View details for PubMedID 25902190

  View details for PubMedCentralID PMC4487548

• Astrocyte-Derived TGF-beta 1 Accelerates Disease Progression in ALS Mice by Interfering with the Neuroprotective Functions of Microglia and T Cells CELL REPORTS Endo, F., Komine, O., Fujimori-Tonou, N., Katsuno, M., Jin, S., Watanabe, S., Sobue, G., Dezawa, M., Wyss-Coray, T., Yamanaka, K. 2015; 11 (4): 592-604

  Abstract

  Neuroinflammation, which includes both neuroprotective and neurotoxic reactions by activated glial cells and infiltrated immune cells, is involved in the pathomechanism of amyotrophic lateral sclerosis (ALS). However, the cytokines that regulate the neuroprotective inflammatory response in ALS are not clear. Here, we identify transforming growth factor-β1 (TGF-β1), which is upregulated in astrocytes of murine and human ALS, as a negative regulator of neuroprotective inflammatory response. We demonstrate that astrocyte-specific overproduction of TGF-β1 in SOD1(G93A) mice accelerates disease progression in a non-cell-autonomous manner, with reduced IGF-I production in deactivated microglia and fewer T cells with an IFN-γ-dominant milieu. Moreover, expression levels of endogenous TGF-β1 in SOD1(G93A) mice negatively correlate with lifespan. Furthermore, pharmacological administration of a TGF-β signaling inhibitor after disease onset extends survival time of SOD1(G93A) mice. These findings indicate that astrocytic TGF-β1 determines disease progression and is critical to the pathomechanism of ALS.

  View details for DOI 10.1016/j.celrep.2015.03.053

  View details for Web of Science ID 000353902600009

  View details for PubMedID 25892237

• Neuroinflammation in Alzheimer's disease LANCET NEUROLOGY Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., Town, T., Morgan, D., Shinohara, M. L., Perry, V. H., Holmes, C., Bazan, N. G., Brooks, D. J., Hunot, S., Joseph, B., Deigendesch, N., Garaschuk, O., Boddeke, E., Dinarello, C. A., Breitner, J. C., Cole, G. M., Golenbock, D. T., Kummer, M. P. 2015; 14 (4): 388-405

  View details for Web of Science ID 000351892400014

• Neuroinflammation in Alzheimer's disease. The Lancet. Neurology Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., Jacobs, A. H., Wyss-Coray, T., Vitorica, J., Ransohoff, R. M., Herrup, K., Frautschy, S. A., Finsen, B., Brown, G. C., Verkhratsky, A., Yamanaka, K., Koistinaho, J., Latz, E., Halle, A., Petzold, G. C., Town, T., Morgan, D., Shinohara, M. L., Perry, V. H., Holmes, C., Bazan, N. G., Brooks, D. J., Hunot, S., Joseph, B., Deigendesch, N., Garaschuk, O., Boddeke, E., Dinarello, C. A., Breitner, J. C., Cole, G. M., Golenbock, D. T., Kummer, M. P. 2015; 14 (4): 388-405

  Abstract

  Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

  View details for DOI 10.1016/S1474-4422(15)70016-5

  View details for PubMedID 25792098

• Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kirby, E. D., Kuwahara, A. A., Messer, R. L., Wyss-Coray, T. 2015; 112 (13): 4128-4133

  Abstract

  The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.

  View details for DOI 10.1073/pnas.1422448112

  View details for Web of Science ID 000351914500079

  View details for PubMedID 25775598

  View details for PubMedCentralID PMC4386397

• PET Imaging of Translocator Protein (18 kDa) in a Mouse Model of Alzheimer's Disease Using N-(2,5-Dimethoxybenzyl)-2-18F-Fluoro-N-(2-Phenoxyphenyl)Acetamide. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Belichenko, N. P., Nguyen, T. V., Andrews, L. E., Ding, Z., Liu, H., Bodapati, D., Arksey, N., Shen, B., Cheng, Z., Wyss-Coray, T., Gambhir, S. S., Longo, F. M., Chin, F. T. 2015; 56 (2): 311-316

  Abstract

  Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-(18)F-fluoro-N-(2-phenoxyphenyl)acetamide ((18)F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD).Wild-type (wt) and AD mice (i.e., APP(L/S)) underwent (18)F-PBR06 PET imaging at predetermined time points between the ages of 5-6 and 15-16 mo. MR images were fused with PET/CT data to quantify (18)F-PBR06 uptake in the hippocampus and cortex. Ex vivo autoradiography and TSPO/CD68 immunostaining were also performed using brain tissue from these mice.PET images showed significantly higher accumulation of (18)F-PBR06 in the cortex and hippocampus of 15- to 16-mo-old APP(L/S) mice than age-matched wts (cortex/muscle: 2.43 ± 0.19 vs. 1.55 ± 0.15, P < 0.005; hippocampus/muscle: 2.41 ± 0.13 vs. 1.55 ± 0.12, P < 0.005). And although no significant difference was found between wt and APP(L/S) mice aged 9-10 mo or less using PET (P = 0.64), we were able to visualize and quantify a significant difference in (18)F-PBR06 uptake in these mice using autoradiography (cortex/striatum: 1.13 ± 0.04 vs. 0.96 ± 0.01, P < 0.05; hippocampus/striatum: 1.266 ± 0.003 vs. 1.096 ± 0.017, P < 0.001). PET results for 15- to 16-mo-old mice correlated well with autoradiography and immunostaining (i.e., increased (18)F-PBR06 uptake in brain regions containing elevated CD68 and TSPO staining in APP(L/S) mice, compared with wts).(18)F-PBR06 shows great potential as a tool for visualizing TSPO/microglia in the progression and treatment of AD.

  View details for DOI 10.2967/jnumed.114.141648

  View details for PubMedID 25613536

• Beclin 1 regulates neuronal transforming growth factor-ß signaling by mediating recycling of the type I receptor ALK5. Molecular neurodegeneration O'Brien, C. E., Bonanno, L., Zhang, H., Wyss-Coray, T. 2015; 10 (1): 69-?

  Abstract

  Beclin 1 is a key regulator of multiple trafficking pathways, including autophagy and receptor recycling in yeast and microglia. Decreased beclin 1 levels in the CNS result in neurodegeneration, an effect attributed to impaired autophagy. However, neurons also rely heavily on trophic factors, and signaling through these pathways requires the proper trafficking of trophic factor receptors.We discovered that beclin 1 regulates signaling through the neuroprotective TGF-β pathway. Beclin 1 is required for recycling of the type I TGF-β receptor ALK5. We show that beclin 1 recruits the retromer to ALK5 and facilitates its localization to Rab11(+) endosomes. Decreased levels of beclin 1, or its binding partners VPS34 and UVRAG, impair TGF-β signaling.These findings identify beclin 1 as a positive regulator of a trophic signaling pathway via receptor recycling, and suggest that neuronal death induced by decreased beclin 1 levels may also be due to impaired trophic factor signaling.

  View details for DOI 10.1186/s13024-015-0065-0

  View details for PubMedID 26692002

  View details for PubMedCentralID PMC4687091

• The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging. Cold Spring Harbor perspectives in medicine DeCarolis, N. A., Kirby, E. D., Wyss-Coray, T., Palmer, T. D. 2015; 5 (12)

  Abstract

  Aging is strongly correlated with decreases in neurogenesis, the process by which neural stem and progenitor cells proliferate and differentiate into new neurons. In addition to stem-cell-intrinsic factors that change within the aging stem-cell pool, recent evidence emphasizes new roles for systemic and microenvironmental factors in modulating the neurogenic niche. This article focuses on new insights gained through the use of heterochronic parabiosis models, in which an old mouse and a young circulatory system are joined. By studying the brains of both young and old mice, researchers are beginning to uncover circulating proneurogenic "youthful" factors and "aging" factors that decrease stem-cell activity and neurogenesis. Ultimately, the identification of factors that influence stem-cell aging may lead to strategies that slow or even reverse age-related decreases in neural-stem-cell (NSC) function and neurogenesis.

  View details for DOI 10.1101/cshperspect.a025874

  View details for PubMedID 26627453

• Geroscience: Linking Aging to Chronic Disease CELL Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., Rando, T. A., Richardson, A., Schadt, E. E., Wyss-Coray, T., Sierra, F. 2014; 159 (4): 708–12

  Abstract

  Mammalian aging can be delayed with genetic, dietary, and pharmacologic approaches. Given that the elderly population is dramatically increasing and that aging is the greatest risk factor for a majority of chronic diseases driving both morbidity and mortality, it is critical to expand geroscience research directed at extending human healthspan.

  View details for PubMedID 25417146

  View details for PubMedCentralID PMC4852871

• Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome PAIN Li, W., Guo, T., Shi, X., Czirr, E., Stan, T., Sahbaie, P., Wyss-Coray, T., Kingery, W. S., Clark, J. D. 2014; 155 (11): 2377-2389

  Abstract

  Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (μMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, μMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in μMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS.

  View details for DOI 10.1016/j.pain.2014.09.007

  View details for Web of Science ID 000345413400020

  View details for PubMedCentralID PMC4252476

• Autoimmunity contributes to nociceptive sensitization in a mouse model of complex regional pain syndrome. Pain Li, W., Guo, T., Shi, X., Czirr, E., Stan, T., Sahbaie, P., Wyss-Coray, T., Kingery, W. S., Clark, J. D. 2014; 155 (11): 2377-2389

  Abstract

  Complex regional pain syndrome (CRPS) is a painful, disabling, chronic condition whose etiology remains poorly understood. The recent suggestion that immunological mechanisms may underlie CRPS provides an entirely novel framework in which to study the condition and consider new approaches to treatment. Using a murine fracture/cast model of CRPS, we studied the effects of B-cell depletion using anti-CD20 antibodies or by performing experiments in genetically B-cell-deficient (μMT) mice. We observed that mice treated with anti-CD20 developed attenuated vascular and nociceptive CRPS-like changes after tibial fracture and 3 weeks of cast immobilization. In mice with established CRPS-like changes, the depletion of CD-20+ cells slowly reversed nociceptive sensitization. Correspondingly, μMT mice, deficient in producing immunoglobulin M (IgM), failed to fully develop CRPS-like changes after fracture and casting. Depletion of CD20+ cells had no detectable effects on nociceptive sensitization in a model of postoperative incisional pain, however. Immunohistochemical experiments showed that CD20+ cells accumulate near the healing fracture but few such cells collect in skin or sciatic nerves. On the other hand, IgM-containing immune complexes were deposited in skin and sciatic nerve after fracture in wild-type, but not in μMT fracture/cast, mice. Additional experiments demonstrated that complement system activation and deposition of membrane attack complexes were partially blocked by anti-CD20+ treatment. Collectively, our results suggest that CD20-positive B cells produce antibodies that ultimately support the CRPS-like changes in the murine fracture/cast model. Therapies directed at reducing B-cell activity may be of use in treating patients with CRPS.

  View details for DOI 10.1016/j.pain.2014.09.007

  View details for PubMedID 25218828

• Aging-induced type I interferon response at the choroid plexus negatively affects brain function SCIENCE Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., Amit, I., Schwartz, M. 2014; 346 (6205): 89-93

  Abstract

  Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.

  View details for DOI 10.1126/science.1252945

  View details for Web of Science ID 000342446900057

• Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., Amit, I., Schwartz, M. 2014; 346 (6205): 89-93

  Abstract

  Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.

  View details for DOI 10.1126/science.1252945

  View details for PubMedID 25147279

• Effects of the Absence of Apolipoprotein E on Lipoproteins, Neurocognitive Function, and Retinal Function JAMA NEUROLOGY Mak, A. C., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., Poon, A., Kim, P., Stock, E. O., Schaefer, E. J., Asztalos, B. F., Castellano, J. M., Wyss-Coray, T., Duncan, J. L., Miller, B. L., Kane, J. P., Kwok, P., Malloy, M. J. 2014; 71 (10): 1228-1236

  Abstract

  The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

  View details for DOI 10.1001/jamaneurol.2014.2011

  View details for Web of Science ID 000343868100006

• Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA neurology Mak, A. C., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., Poon, A., Kim, P., Stock, E. O., Schaefer, E. J., Asztalos, B. F., Castellano, J. M., Wyss-Coray, T., Duncan, J. L., Miller, B. L., Kane, J. P., Kwok, P., Malloy, M. J. 2014; 71 (10): 1228-1236

  Abstract

  The identification of a patient with a rare form of severe dysbetalipoproteinemia allowed the study of the consequences of total absence of apolipoprotein E (apoE).To discover the molecular basis of this rare disorder and to determine the effects of complete absence of apoE on neurocognitive and visual function and on lipoprotein metabolism.Whole-exome sequencing was performed on the patient's DNA. He underwent detailed neurological and visual function testing and lipoprotein analysis. Lipoprotein analysis was also performed in the Cardiovascular Research Institute, University of California, San Francisco, on blood samples from the proband's mother, wife, 2 daughters, and normolipidemic control participants.Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). No other mutations likely to contribute to the phenotype were discovered, with the possible exception of two, in ABCC2 (p.I670T) and LIPC (p.G137R). Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high cholesterol content (760 mg/dL; to convert to millimoles per liter, multiply by 0.0259) and a high cholesterol to triglycerides ratio (1.52) in very low-density lipoproteins with elevated levels of small-diameter high-density lipoproteins, including high levels of prebeta-1 high-density lipoprotein. Intermediate-density lipoproteins, low-density lipoproteins, and very low-density lipoproteins contained elevated apoA-I and apoA-IV levels. The patient's apoC-III and apoC-IV levels were decreased in very low-density lipoproteins. Electron microscopy revealed large lamellar particles having electron-opaque cores attached to electron-lucent zones in intermediate-density and low-density lipoproteins. Low-density lipoprotein particle diameters were distributed bimodally.Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled. Targeted knockdown of apoE in the central nervous system might be a therapeutic modality in neurodegenerative disorders.

  View details for DOI 10.1001/jamaneurol.2014.2011

  View details for PubMedID 25111166

• TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis SCIENCE TRANSLATIONAL MEDICINE Kleinberger, G., Yamanishi, Y., Suarez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., Tahirovic, S., Lleo, A., Alcolea, D., Fortea, J., Willem, M., Lammich, S., Molinuevo, J. L., Sanchez-Valle, R., Antonell, A., Ramirez, A., Heneka, M. T., Sleegers, K., van der Zee, J., Martin, J., Engelborghs, S., Demirtas-Tatlidede, A., Zetterberg, H., Van Broeckhoven, C., Gurvit, H., Wyss-Coray, T., Hardy, J., Colonna, M., Haass, C. 2014; 6 (243)

  Abstract

  Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.

  View details for DOI 10.1126/scitranslmed.3009093

  View details for Web of Science ID 000338712200006

  View details for PubMedID 24990881

• ALK5-dependent TGF-beta signaling is a major determinant of late-stage adult neurogenesis NATURE NEUROSCIENCE He, Y., Zhang, H., Yung, A., Villeda, S. A., Jaeger, P. A., Olayiwola, O., Fainberg, N., Wyss-Coray, T. 2014; 17 (7): 943-952

  Abstract

  The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in CNS development, but, apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a marked increase in these aspects of neurogenesis and was associated with higher expression of c-Fos in newborn neurons and with stronger memory function. Our findings describe an unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis, which may have implications for changes in neurogenesis during aging and disease.

  View details for DOI 10.1038/nn.3732

  View details for PubMedID 24859199

• Stem cells as vehicles for youthful regeneration of aged tissues. journals of gerontology. Series A, Biological sciences and medical sciences Rando, T. A., Wyss-Coray, T. 2014; 69: S39-42

  Abstract

  Stem cells hold great promise for regenerative therapies for a wide spectrum of diseases and disorders of aging by virtue of their ability to regenerate tissues and contribute to their homeostasis. Aging is associated with a marked decline in these functionalities of adult stem cells. As such, regeneration of aged tissues is both less efficient and less effective than that of young tissues. Recent studies have revealed the remarkably dynamic responses of stem cells to systemic signals, including the ability of "youthful" factors in the blood of young animals to enhance the functionality of aged stem cells. Thus, there is much hope that even aged stem cells retain a remarkable regenerative potential if provided with the correct cues and environment to engage in tissue repair. The overall focus of the presentations of this session is to address the determinants of changes in stem cell functionality with age, the key characteristics of stem cells in aged tissues, the extent to which those characteristics are capable of being rejuvenated and by what signals, and the potential for stem cell therapeutics for chronic diseases and acute injuries in aged individuals.

  View details for DOI 10.1093/gerona/glu043

  View details for PubMedID 24833585

  View details for PubMedCentralID PMC4022127

• Stem cells as vehicles for youthful regeneration of aged tissues. journals of gerontology. Series A, Biological sciences and medical sciences Rando, T. A., Wyss-Coray, T. 2014; 69: S39-42

  View details for DOI 10.1093/gerona/glu043

  View details for PubMedID 24833585

• Sorting Through the Roles of Beclin 1 in Microglia and Neurodegeneration JOURNAL OF NEUROIMMUNE PHARMACOLOGY O'Brien, C. E., Wyss-Coray, T. 2014; 9 (3): 285-292

  Abstract

  Beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway. Although the yeast ortholog of beclin 1 (Atg6/Vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. We recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. Microglia lacking beclin 1 have a reduced phagocytic capacity, which impairs clearance of amyloid β (Aβ) in a mouse model of Alzheimer's Disease (AD). Here we summarize these findings and discuss the implications for beclin 1-regulated receptor recycling in neurodegenerative disease.

  View details for DOI 10.1007/s11481-013-9519-8

  View details for Web of Science ID 000335671000003

  View details for PubMedID 24385262

  View details for PubMedCentralID PMC4019692

• Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature medicine Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B., Simmons, D. A., Xie, X. S., Longo, F. M., Wyss-Coray, T. 2014; 20 (6): 659-663

  Abstract

  As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

  View details for DOI 10.1038/nm.3569

  View details for PubMedID 24793238

  View details for PubMedCentralID PMC4224436

• Noninvasive in vivo monitoring of tissue-specific global gene expression in humans. Proceedings of the National Academy of Sciences of the United States of America Koh, W., Pan, W., Gawad, C., Fan, H. C., Kerchner, G. A., Wyss-Coray, T., Blumenfeld, Y. J., El-Sayed, Y. Y., Quake, S. R. 2014; 111 (20): 7361-7366

  Abstract

  Circulating cell-free RNA in the blood provides a potential window into the health, phenotype, and developmental programs of a variety of human organs. We used high-throughput methods of RNA analysis such as microarrays and next-generation sequencing to characterize the global landscape circulating RNA in a cohort of human subjects. By focusing on genes whose expression is highly specific to certain tissues, we were able to identify the relative contributions of these tissues to circulating RNA and to monitor changes in tissue development and health. As one application of this approach, we performed a longitudinal study on pregnant women and analyzed their combined cell-free RNA transcriptomes across all three trimesters of pregnancy and after delivery. In addition to the analysis of mRNA, we observed and characterized noncoding species such as long noncoding RNA and circular RNA transcripts whose presence had not been previously observed in human plasma. We demonstrate that it is possible to track specific longitudinal phenotypic changes in both the mother and the fetus and that it is possible to directly measure transcripts from a variety of fetal tissues in the maternal blood sample. We also studied the role of neuron-specific transcripts in the blood of healthy adults and those suffering from the neurodegenerative disorder Alzheimer's disease and showed that disease specific neural transcripts are present at increased levels in the blood of affected individuals. Characterization of the cell-free transcriptome in its entirety may thus provide broad insights into human health and development without the need for invasive tissue sampling.

  View details for DOI 10.1073/pnas.1405528111

  View details for PubMedID 24799715

• Microglial dysfunction in brain aging and Alzheimer's disease BIOCHEMICAL PHARMACOLOGY Mosher, K. I., Wyss-Coray, T. 2014; 88 (4): 594-604

  Abstract

  Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

  View details for DOI 10.1016/j.bcp.2014.01.008

  View details for Web of Science ID 000334977400018

  View details for PubMedID 24445162

  View details for PubMedCentralID PMC3972294

• APOE {varepsilon}4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology Kerchner, G. A., Berdnik, D., Shen, J. C., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Wyss-Coray, T., Rutt, B. K. 2014; 82 (8): 691-697

  Abstract

  Using high-resolution structural MRI, we endeavored to study the relationships among APOE ε4, hippocampal subfield and stratal anatomy, and episodic memory.Using a cross-sectional design, we studied 11 patients with Alzheimer disease dementia, 14 patients with amnestic mild cognitive impairment, and 14 age-matched healthy controls with no group differences in APOE ε4 carrier status. Each subject underwent ultra-high-field 7.0-tesla MRI targeted to the hippocampus and neuropsychological assessment.We found a selective, dose-dependent association of APOE ε4 with greater thinning of the CA1 apical neuropil, or stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), a hippocampal subregion known to exhibit early vulnerability to neurofibrillary pathology in Alzheimer disease. The relationship between the ε4 allele and CA1-SRLM thinning persisted after controlling for dementia severity, and the size of other hippocampal subfields and the entorhinal cortex did not differ by APOE ε4 carrier status. Carriers also exhibited worse episodic memory function but similar performance in other cognitive domains compared with noncarriers. In a statistical mediation analysis, we found support for the hypothesis that CA1-SRLM thinning may link the APOE ε4 allele to its phenotypic effects on memory.The APOE ε4 allele segregated dose-dependently and selectively with CA1-SRLM thinning and worse episodic memory performance in a pool of older subjects across a cognitive spectrum. These findings highlight a possible role for this gene in influencing a critical hippocampal subregion and an associated symptomatic manifestation.

  View details for DOI 10.1212/WNL.0000000000000154

  View details for PubMedID 24453080

• Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. journal of experimental medicine Ding, Z., Mathur, V., Ho, P. P., James, M. L., Lucin, K. M., Hoehne, A., Alabsi, H., Gambhir, S. S., Steinman, L., Luo, J., Wyss-Coray, T. 2014; 211 (2): 189-198

  Abstract

  Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid-induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, [(18)F]FHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties.

  View details for DOI 10.1084/jem.20120696

  View details for PubMedID 24493798

  View details for PubMedCentralID PMC3920559

• The future of blood-based biomarkers for Alzheimer's disease ALZHEIMERS & DEMENTIA Henriksen, K., O'Bryant, S. E., Hamper, H., Trojanowski, J. Q., Montine, T. J., Jeromin, A., Blennow, K., Lonneborg, A., Wyss-Coray, T., Soares, H., Bazenet, C., Sjogren, M., Hu, W., Lovestone, S., Karsdal, M. A., Weiner, M. W. 2014; 10 (1): 115-131

  Abstract

  Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

  View details for DOI 10.1016/j.jalz.2013.01.013

  View details for Web of Science ID 000329559300015

  View details for PubMedID 23850333

• Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury FRONTIERS IN NEUROLOGY Luo, J., Nguyen, A., Villeda, S., Zhang, H., Ding, Z., Lindsey, D., Bieri, G., Castellano, J. M., Beaupre, G. S., Wyss-Coray, T. 2014; 5

  View details for DOI 10.3389/fneur.2014.00012

  View details for Web of Science ID 000209629300012

• Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in AßPP(L/S) transgenic mice. Journal of Alzheimer's disease : JAD Nguyen, T. V., Shen, L., Vander Griend, L., Quach, L. N., Belichenko, N. P., Saw, N., Yang, T., Shamloo, M., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2014; 42 (2): 459-483

  Abstract

  The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

  View details for DOI 10.3233/JAD-140036

  View details for PubMedID 24898660

• Small Molecule p75(NTR) Ligands Reduce Pathological Phosphorylation and Misfolding of Tau, Inflammatory Changes, Cholinergic Degeneration, and Cognitive Deficits in A beta PPL/S Transgenic Mice JOURNAL OF ALZHEIMERS DISEASE Nguyen, T. V., Shen, L., Vander Griend, L., Quach, L. N., Belichenko, N. P., Saw, N., Yang, T., Shamloo, M., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2014; 42 (2): 459-483

  Abstract

  The p75 neurotrophin receptor (p75NTR) is involved in degenerative mechanisms related to Alzheimer's disease (AD). In addition, p75NTR levels are increased in AD and the receptor is expressed by neurons that are particularly vulnerable in the disease. Therefore, modulating p75NTR function may be a significant disease-modifying treatment approach. Prior studies indicated that the non-peptide, small molecule p75NTR ligands LM11A-31, and chemically unrelated LM11A-24, could block amyloid-β-induced deleterious signaling and neurodegeneration in vitro, and LM11A-31 was found to mitigate neuritic degeneration and behavioral deficits in a mouse model of AD. In this study, we determined whether these in vivo findings represent class effects of p75NTR ligands by examining LM11A-24 effects. In addition, the range of compound effects was further examined by evaluating tau pathology and neuroinflammation. Following oral administration, both ligands reached brain concentrations known to provide neuroprotection in vitro. Compound induction of p75NTR cleavage provided evidence for CNS target engagement. LM11A-31 and LM11A-24 reduced excessive phosphorylation of tau, and LM11A-31 also inhibited its aberrant folding. Both ligands decreased activation of microglia, while LM11A-31 attenuated reactive astrocytes. Along with decreased inflammatory responses, both ligands reduced cholinergic neurite degeneration. In addition to the amelioration of neuropathology in AD model mice, LM11A-31, but not LM11A-24, prevented impairments in water maze performance, while both ligands prevented deficits in fear conditioning. These findings support a role for p75NTR ligands in preventing fundamental tau-related pathologic mechanisms in AD, and further validate the development of these small molecules as a new class of therapeutic compounds.

  View details for DOI 10.3233/JAD-140036

  View details for Web of Science ID 000341572000012

• Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury. Frontiers in neurology Luo, J., Nguyen, A., Villeda, S., Zhang, H., Ding, Z., Lindsey, D., Bieri, G., Castellano, J. M., Beaupre, G. S., Wyss-Coray, T. 2014; 5: 12-?

  Abstract

  Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all traumatic brain injuries. The consequences of repetitive mTBI have become of particular concern for individuals engaged in certain sports or in military operations. Many mTBI patients suffer long-lasting neurobehavioral impairments. In order to expedite pre-clinical research and therapy development, there is a need for animal models that reflect the long-term cognitive and pathological features seen in patients. In the present study, we developed and characterized a mouse model of repetitive mTBI, induced onto the closed head over the left frontal hemisphere with an electromagnetic stereotaxic impact device. Using GFAP-luciferase bioluminescence reporter mice that provide a readout of astrocyte activation, we observed an increase in bioluminescence relative to the force delivered by the impactor after single impact and cumulative effects of repetitive mTBI. Using the injury parameters established in the reporter mice, we induced a repetitive mTBI in wild-type C57BL/6J mice and characterized the long-term outcome. Animals received repetitive mTBI showed a significant impairment in spatial learning and memory when tested at 2 and 6 months after injury. A robust astrogliosis and increased p-Tau immunoreactivity were observed upon post-mortem pathological examinations. These findings are consistent with the deficits and pathology associated with mTBI in humans and support the use of this model to evaluate potential therapeutic approaches.

  View details for DOI 10.3389/fneur.2014.00012

  View details for PubMedID 24550885

  View details for PubMedCentralID PMC3912443

• A revival of parabiosis in biomedical research. Swiss medical weekly Eggel, A., Wyss-Coray, T. 2014; 144: w13914-?

  Abstract

  Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer's disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century. Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

  View details for DOI 10.4414/smw.2014.13914

  View details for PubMedID 24496774

• Chronic Over-Expression of TGF beta 1 Alters Hippocampal Structure and Causes Learning Deficits HIPPOCAMPUS Martinez-Canabal, A., Wheeler, A. L., Sarkis, D., Lerch, J. P., Lu, W., Buckwalter, M. S., Wyss-Coray, T., Josselyn, S. A., Frankland, P. W. 2013; 23 (12): 1198-1211

  Abstract

  The cytokine Transforming Growth Factor β1 (TGFβ1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. While previous studies have shown that TGFβ1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFβ1 in isolation we used transgenic mice that over-express a constitutively active porcine TGFβ1 in astrocytes. We found that TGFβ1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG micro- and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFβ1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFβ1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/hipo.22159

  View details for Web of Science ID 000327157200007

  View details for PubMedID 23804429

• Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron Lucin, K. M., O'Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. 2013; 79 (5): 873-886

  Abstract

  Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

  View details for DOI 10.1016/j.neuron.2013.06.046

  View details for PubMedID 24012002

  View details for PubMedCentralID PMC3779465

• Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron Lucin, K. M., O'Brien, C. E., Bieri, G., Czirr, E., Mosher, K. I., Abbey, R. J., Mastroeni, D. F., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. 2013; 79 (5): 873-886

  Abstract

  Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis in vitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer's disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD.

  View details for DOI 10.1016/j.neuron.2013.06.046

  View details for PubMedID 24012002

  View details for PubMedCentralID PMC3779465

• TDP-43 frontotemporal lobar degeneration and autoimmune disease JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Miller, Z. A., Rankin, K. P., Graff-Radford, N. R., Takada, L. T., Sturm, V. E., Cleveland, C. M., Criswell, L. A., Jaeger, P. A., Stan, T., Heggeli, K. A., Hsu, S. C., Karydas, A., Khan, B. K., Grinberg, L. T., Gorno-Tempini, M. L., Boxer, A. L., Rosen, H. J., Kramer, J. H., Coppola, G., Geschwind, D. H., Rademakers, R., Seeley, W. W., Wyss-Coray, T., Miller, B. L. 2013; 84 (9): 956-962

  Abstract

  BACKGROUND: The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. OBJECTIVE: To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. DESIGN: Case control. SETTING: Academic medical centres. PARTICIPANTS: 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) Comparison of autoimmune prevalence and follow-up logistic regression. RESULTS: There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.

  View details for DOI 10.1136/jnnp-2012-304644

  View details for Web of Science ID 000323164000007

  View details for PubMedID 23543794

• A small molecule p75(NTR) ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiology of aging Knowles, J. K., Simmons, D. A., Nguyen, T. V., Vander Griend, L., Xie, Y., Zhang, H., Yang, T., Pollak, J., Chang, T., Arancio, O., Buckwalter, M. S., Wyss-Coray, T., Massa, S. M., Longo, F. M. 2013; 34 (8): 2052-2063

  Abstract

  The p75 neurotrophin receptor (p75(NTR)) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75(NTR) ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75(NTR) ligand, LM11A-31, was administered orally to the Thy-1 hAPP(Lond/Swe) (APP(L/S)) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APP(L/S) mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75(NTR) is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.

  View details for DOI 10.1016/j.neurobiolaging.2013.02.015

  View details for PubMedID 23545424

• Targeting autophagy for disease therapy. Nature biotechnology Lucin, K. M., Wyss-Coray, T. 2013; 31 (4): 322-323

  View details for DOI 10.1038/nbt.2554

  View details for PubMedID 23563430

• The circulatory systemic environment as a modulator of neurogenesis and brain aging. Autoimmunity reviews Villeda, S. A., Wyss-Coray, T. 2013; 12 (6): 674-677

  Abstract

  The ability of the adult brain to generate newly born neurons dramatically declines during aging, and has even been proposed to contribute, in part, to age-related cognitive impairments. While intrinsic molecular mechanisms underlying decreased neurogenesis during aging have begun to be elucidated, relatively little is still known as to the contribution of the systemic environment. Interestingly, immune signaling has quickly emerged as a key negative regulator of adult neurogenesis, and has more recently been functionally linked to the aging circulatory systemic environment. In this review we examine the role of the aging systemic environment in regulating adult neurogenesis and cognitive function. We discuss recent work from our group using the aging model of heterochronic parabiosis - in which the circulatory system of two animals is connected - to highlight the contribution of circulatory immune factors to age-related impairments in adult neurogenesis and associated cognitive processes. Finally, we propose the possibility of combating brain aging by tapping into the 'rejuvenating' potential inherent in a young circulatory systemic environment.

  View details for DOI 10.1016/j.autrev.2012.10.014

  View details for PubMedID 23201925

• Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival JOURNAL OF EXPERIMENTAL MEDICINE Luo, J., Elwood, F., Britschgi, M., Villeda, S., Zhang, H., Ding, Z., Zhu, L., Alabsi, H., Getachew, R., Narasimhan, R., Wabl, R., Fainberg, N., James, M. L., Wong, G., Relton, J., Gambhir, S. S., Pollard, J. W., Wyss-Coray, T. 2013; 210 (1): 157-172

  Abstract

  Colony-stimulating factor 1 (CSF1) and interleukin-34 (IL-34) are functional ligands of the CSF1 receptor (CSF1R) and thus are key regulators of the monocyte/macrophage lineage. We discovered that systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer's disease. CSF1 and IL-34 strongly reduced excitotoxin-induced neuronal cell loss and gliosis in wild-type mice when administered systemically before or up to 6 h after injury. These effects were accompanied by maintenance of cAMP responsive element-binding protein (CREB) signaling in neurons rather than in microglia. Using lineage-tracing experiments, we discovered that a small number of neurons in the hippocampus and cortex express CSF1R under physiological conditions and that kainic acid-induced excitotoxic injury results in a profound increase in neuronal receptor expression. Selective deletion of CSF1R in forebrain neurons in mice exacerbated excitotoxin-induced death and neurodegeneration. We conclude that CSF1 and IL-34 provide powerful neuroprotective and survival signals in brain injury and neurodegeneration involving CSF1R expression on neurons.

  View details for DOI 10.1084/jem.20120412

  View details for Web of Science ID 000313560900014

  View details for PubMedID 23296467

  View details for PubMedCentralID PMC3549715

• Changes of the Enteric Nervous System in Amyloid-beta Protein Precursor Transgenic Mice Correlate with Disease Progression JOURNAL OF ALZHEIMERS DISEASE Semar, S., Klotz, M., Letiembre, M., Van Ginneken, C., Braun, A., Jost, V., Bischof, M., Lammers, W. J., Liu, Y., Fassbender, K., Wyss-Coray, T., Kirchhoff, F., Schaefer, K. 2013; 36 (1): 7-20

  Abstract

  In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches.

  View details for DOI 10.3233/JAD-120511

  View details for Web of Science ID 000320030200002

  View details for PubMedID 23531500

• The role of inflammation in age-related disease AGING-US Howcroft, T. K., Campisi, J., Louis, G. B., Smith, M. T., Wise, B., Wyss-Coray, T., Augustine, A. D., McElhaney, J. E., Kohanski, R., Sierra, F. 2013; 5 (1): 84-93

  Abstract

  The National Institutes of Health (NIH) Geroscience Interest Group (GSIG) sponsored workshop, The Role of Inflammation inAge-Related Disease, was held September 6th-7th, 2012 in Bethesda, MD. It is now recognized that a mild pro-inflammatory state is correlated with the major degenerative diseases of the elderly. The focus of the workshop was to better understand the origins and consequences of this low level chronic inflammation in order to design appropriate interventional studies aimed at improving healthspan. Four sessions explored the intrinsic, environmental exposures and immune pathways by which chronic inflammation are generated, sustained, and lead to age-associated diseases. At the conclusion of the workshop recommendations to accelerate progress toward understanding the mechanistic bases of chronic disease were identified.

  View details for Web of Science ID 000315982300007

  View details for PubMedID 23474627

• beta 2-microglobulin regulates the age-related decline in adult neurogenesis and cognitive function 11th International Congress of Neuroimmunology (ISNI) Villeda, S., Park, J., He, Y., Wabl, R., Bieri, G., Luo, J., Grant, J., Wyss-Coray, T. ELSEVIER SCIENCE BV. 2012: 159–60

  View details for Web of Science ID 000312764800428

• Changes in beclin 1 associated with Alzheimer's disease negatively regulate retromer and impair phagocytosis of amyloid-beta 11th International Congress of Neuroimmunology (ISNI) Lucin, K., O'Brien, C., Bieri, G., Czirr, E., Mosher, K., Mastroeni, D., Rogers, J., Spencer, B., Masliah, E., Wyss-Coray, T. ELSEVIER SCIENCE BV. 2012: 104–

  View details for Web of Science ID 000312764800277

• Neural progenitor cells regulate microglia functions and activity NATURE NEUROSCIENCE Mosher, K. I., Andres, R. H., Fukuhara, T., Bieri, G., Hasegawa-Moriyama, M., He, Y., Guzman, R., Wyss-Coray, T. 2012; 15 (11): 1485-1487

  Abstract

  We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity.

  View details for DOI 10.1038/nn.3233

  View details for Web of Science ID 000310424900007

  View details for PubMedID 23086334

  View details for PubMedCentralID PMC3495979

• Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice JOURNAL OF NEUROINFLAMMATION Britschgi, M., Takeda-Uchimura, Y., Rockenstein, E., Johns, H., Masliah, E., Wyss-Coray, T. 2012; 9

  Abstract

  The neuronal microtubule-associated protein tau becomes hyperphosphorylated and forms aggregates in tauopathies but the processes leading to this pathological hallmark are not understood. Because tauopathies are accompanied by neuroinflammation and the complement cascade forms a key innate immune pathway, we asked whether the complement system has a role in the development of tau pathology.We tested this hypothesis in two mouse models, which expressed either a central inhibitor of complement or lacked an inhibitor of the terminal complement pathway. Complement receptor-related gene/protein y is the natural inhibitor of the central complement component C3 in rodents. Expressing a soluble variant (sCrry) reduced the number of phospho-tau (AT8 epitope) positive neurons in the brain stem, cerebellum, cortex, and hippocampus of aged P301L mutant tau/sCrry double-transgenic mice compared with tau single-transgenic littermates (JNPL3 line). CD59a is the major inhibitor of formation of the membrane attack complex in mice. Intrahippocampal injection of adeno-associated virus encoding mutant human P301L tau into Cd59a-/- mice resulted in increased numbers of AT8-positive cells compared with wild-type controls. This was accompanied by neuronal and synaptic loss and reduced dendritic integrity.Our data in two independent mouse models with genetic changes in key regulators of the complement system support the hypothesis that the terminal pathway has an active role in the development of tau pathology. We propose that inhibition of the terminal pathway may be beneficial in tauopathies.

  View details for DOI 10.1186/1742-2094-9-220

  View details for Web of Science ID 000311733500001

  View details for PubMedID 22989354

  View details for PubMedCentralID PMC3511294

• The 1st International standard for transforming growth factor-beta 3 (TGF-beta 3) JOURNAL OF IMMUNOLOGICAL METHODS Wadhwa, M., Dilger, P., Hamill, M., Bending, D., Gibbs, S., Wu, G., Read, J., Wyss-Coray, T., Zhang, H., Little, J., Getliffe, K. M., Kai, G., Wang, W., Bender, D., Bird, C., Heath, A. B., Cooke, A., Thorpe, R. 2012; 380 (1-2): 1-9

  Abstract

  One candidate preparation of human sequence recombinant transforming growth factor-β3 (TGF-β3) was formulated and lyophilized at NIBSC prior to evaluation in a collaborative study for its suitability to serve as an international standard. The preparation was tested by 8 laboratories using in vitro bioassays and immunoassays. The candidate preparation 09/234 was judged suitable to serve as an international standard based on the data obtained for biological activity and stability. On the basis of the results reported here, the preparation coded 09/234 was established by the WHO Expert Committee on Biological Standardisation (ECBS) as the WHO 1st IS for human TGF-β3 with an assigned value for TGF-β3 activity of 19,000 IU/ampoule.

  View details for DOI 10.1016/j.jim.2012.03.002

  View details for Web of Science ID 000305362300001

  View details for PubMedID 22464938

• Heparan Sulfate Subdomains that are Degraded by Sulf Accumulate in Cerebral Amyloid beta Plaques of Alzheimer's Disease Evidence from Mouse Models and Patients AMERICAN JOURNAL OF PATHOLOGY Hosono-Fukao, T., Ohtake-Niimi, S., Hoshino, H., Britschgi, M., Akatsu, H., Hossain, M. M., Nishitsuji, K., van Kuppevelt, T. H., Kimata, K., Michikawa, M., Wyss-Coray, T., Uchimura, K. 2012; 180 (5): 2056-2067

  Abstract

  Alzheimer's disease (AD) is characterized by extracellular cerebral accumulation of amyloid β peptide (Aβ). Heparan sulfate (HS) is a glycosaminoglycan that is abundant in the extracellular space. The state of sulfation within the HS chain influences its ability to interact with a variety of proteins. Highly sulfated domains within HS are crucial for Aβ aggregation in vitro. Here, we investigated the expression of the sulfated domains and HS disaccharide composition in the brains of Tg2576, J20, and T41 transgenic AD mouse models, and patients with AD. RB4CD12, a phage display antibody, recognizes highly sulfated domains of HS. The RB4CD12 epitope is abundant in the basement membrane of brain vessels under physiological conditions. In the cortex and hippocampus of the mice and patients with AD, RB4CD12 strongly stained both diffuse and neuritic amyloid plaques. Interestingly, RB4CD12 also stained the intracellular granules of certain hippocampal neurons in AD brains. Disaccharide compositions in vessel-enriched and nonvasculature fractions of Tg2576 mice and AD patients were found to be comparable to those of non-transgenic and non-demented controls, respectively. The RB4CD12 epitope in amyloid plaques was substantially degraded ex vivo by Sulf-1 and Sulf-2, extracellular HS endosulfatases. These results indicate that formation of highly sulfated HS domains may be upregulated in conjunction with AD pathogenesis, and that these domains can be enzymatically remodeled in AD brains.

  View details for DOI 10.1016/j.ajpath.2012.01.015

  View details for Web of Science ID 000303641000029

  View details for PubMedID 22429964

• The immunology of neurodegeneration JOURNAL OF CLINICAL INVESTIGATION Czirr, E., Wyss-Coray, T. 2012; 122 (4): 1156-1163

  Abstract

  While immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. Factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. We will review this complex field from the perspective of neurons, extra-neuronal brain cells, and the systemic environment and highlight the possibility that cell intrinsic innate immune molecules in neurons may function in neurodegenerative processes.

  View details for DOI 10.1172/JCI58656

  View details for Web of Science ID 000302281800007

  View details for PubMedID 22466657

  View details for PubMedCentralID PMC3315444

• Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function. Brain and behavior Faizi, M., Bader, P. L., Saw, N., Nguyen, T. V., Beraki, S., Wyss-Coray, T., Longo, F. M., Shamloo, M. 2012; 2 (2): 142-154

  Abstract

  Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

  View details for DOI 10.1002/brb3.41

  View details for PubMedID 22574282

  View details for PubMedCentralID PMC3345358

• Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function BRAIN AND BEHAVIOR Faizi, M., Bader, P. L., Saw, N., Nguyen, T. V., Beraki, S., Wyss-Coray, T., Longo, F. M., Shamloo, M. 2012; 2 (2): 142-154

  Abstract

  Alzheimer's disease (AD), the most common form of dementia, is an age-dependent progressive neurodegenerative disorder. β-amyloid, a metabolic product of the amyloid precursor protein (APP), plays an important role in the pathogenesis of AD. The Thy1-hAPP(Lond/Swe+) (line 41) transgenic mouse overexpresses human APP751 and contains the London (V717I) and Swedish (K670M/N671L) mutations. Here, we used a battery of behavioral tests to evaluate general activity, cognition, and social behavior in six-month-old male Thy1-hAPP(Lond/Swe+) mice. We found hyperactivity in a novel environment as well as significant deficits in spontaneous alternation behavior. In fear conditioning (FC), Thy1-hAPP(Lond/Swe+) mice did not display deficits in acquisition or in memory retrieval in novel context of tone-cued FC, but they showed significant memory retrieval impairment during contextual testing in an identical environment. Surprisingly, in a standard hidden platform water maze, no significant deficit was detected in mutant mice. However, a delayed-matching-to-place paradigm revealed a significant deficit in Thy1-hAPP(Lond/Swe+) mice. Lastly, in the social novelty session of a three-chamber test, Thy1-hAPP(Lond/Swe+) mice exhibited a significantly decreased interest in a novel versus a familiar stranger compared to control mice. This could possibly be explained by decreased social memory or discrimination and may parallel disturbances in social functioning in human AD patients. In conclusion, the Thy1-hAPP(Lond/Swe+) mouse model of AD displayed a behavioral phenotype that resembles, in part, the cognitive and psychiatric symptoms experienced in AD patients.

  View details for DOI 10.1002/brb3.41

  View details for Web of Science ID 000209173900005

  View details for PubMedCentralID PMC3345358

• Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model NEUROBIOLOGY OF AGING Lifshitz, V., Weiss, R., Benromano, T., Kfir, E., Blumenfeld-Katzir, T., Tempel-Brami, C., Assaf, Y., Xia, W., Wyss-Coray, T., Weiner, H. L., Frenkel, D. 2012; 33 (2)

  Abstract

  Cerebrovascular amyloidosis is caused by amyloid accumulation in walls of blood vessel walls leading to hemorrhagic stroke and cognitive impairment. Transforming growth factor-β1 (TGF-β1) expression levels correlate with the degree of cerebrovascular amyloid deposition in Alzheimer's disease (AD) and TGF-β1 immunoreactivity in such cases is increased along the cerebral blood vessels. Here we show that a nasally administered proteosome-based adjuvant activates macrophages and decreases vascular amyloid in TGF-β1 mice. Animals were nasally treated with a proteosome-based adjuvant on a weekly basis for 3 months beginning at age 13 months. Using magnetic resonance imaging (MRI) we found that while control animals showed a significant cerebrovascular pathology, proteosome-based adjuvant prevents further brain damage and prevents pathological changes in the blood-brain barrier. Using an object recognition test and Y-maze, we found significant improvement in cognition in the treated group. Our findings support the potential use of a macrophage immunomodulator as a novel approach to reduce cerebrovascular amyloid, prevent microhemorrhage, and improve cognition.

  View details for DOI 10.1016/j.neurobiolaging.2011.01.006

  View details for Web of Science ID 000298171800051

  View details for PubMedID 21371785

• Inflammation in Alzheimer Disease-A Brief Review of the Basic Science and Clinical Literature COLD SPRING HARBOR PERSPECTIVES IN MEDICINE Wyss-Coray, T., Rogers, J. 2012; 2 (1)

  Abstract

  Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.

  View details for DOI 10.1101/cshperspect.a006346

  View details for Web of Science ID 000314239200010

  View details for PubMedID 22315714

  View details for PubMedCentralID PMC3253025

• Identification of a central role for complement in osteoarthritis NATURE MEDICINE Wang, Q., Rozelle, A. L., Lepus, C. M., Scanzello, C. R., Song, J. J., Larsen, D. M., Crish, J. F., Bebek, G., Ritter, S. Y., Lindstrom, T. M., Hwang, I., Wong, H. H., Punzi, L., Encarnacion, A., Shamloo, M., Goodman, S. B., Wyss-Coray, T., Goldring, S. R., Banda, N. K., Thurman, J. M., Gobezie, R., Crow, M. K., Holers, V. M., Lee, D. M., Robinson, W. H. 2011; 17 (12): 1674-U196

  Abstract

  Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

  View details for DOI 10.1038/nm.2543

  View details for Web of Science ID 000297978000042

  View details for PubMedID 22057346

  View details for PubMedCentralID PMC3257059

• Modeling of Pathological Traits in Alzheimer's Disease Based on Systemic Extracellular Signaling Proteome MOLECULAR & CELLULAR PROTEOMICS Britschgi, M., Rufibach, K., Huang, S. L., Clark, C. M., Kaye, J. A., Li, G., Peskind, E. R., Quinn, J. F., Galasko, D. R., Wyss-Coray, T. 2011; 10 (10)

  Abstract

  The study of chronic brain diseases including Alzheimer's disease in patients is typically limited to brain imaging or psychometric testing. Given the epidemic rise and insufficient knowledge about pathological pathways in sporadic Alzheimer's disease, new tools are required to identify the molecular changes underlying this disease. We hypothesize that levels of specific secreted cellular signaling proteins in cerebrospinal fluid or plasma correlate with pathological changes in the Alzheimer's disease brain and can thus be used to discover signaling pathways altered in the disease. Here we measured 91 proteins of this subset of the cellular communication proteome in plasma or cerebrospinal fluid in patients with Alzheimer's disease and cognitively normal controls to mathematically model disease-specific molecular traits. We found small numbers of signaling proteins that were able to model key pathological markers of Alzheimer's disease, including levels of cerebrospinal fluid β-amyloid and tau, and classify disease in independent samples. Several of these factors had previously been implicated in Alzheimer's disease supporting the validity of our approach. Our study also points to proteins which were previously unknown to be associated with Alzheimer's disease thereby implicating novel signaling pathways in this disorder.

  View details for DOI 10.1074/mcp.M111.008862

  View details for Web of Science ID 000295773800019

  View details for PubMedID 21742799

  View details for PubMedCentralID PMC3205866

• The ageing systemic milieu negatively regulates neurogenesis and cognitive function NATURE Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., Lucin, K. M., Czirr, E., Park, J., Couillard-Despres, S., Aigner, L., Li, G., Peskind, E. R., Kaye, J. A., Quinn, J. F., Galasko, D. R., Xie, X. S., Rando, T. A., Wyss-Coray, T. 2011; 477 (7362): 90-U157

  Abstract

  In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

  View details for DOI 10.1038/nature10357

  View details for Web of Science ID 000294404300037

  View details for PubMedID 21886162

  View details for PubMedCentralID PMC3170097

• Complement Receptor 2 Is Expressed in Neural Progenitor Cells and Regulates Adult Hippocampal Neurogenesis JOURNAL OF NEUROSCIENCE Moriyama, M., Fukuhara, T., Britschgi, M., He, Y., Narasimhan, R., Villeda, S., Molina, H., Huber, B. T., Holers, M., Wyss-Coray, T. 2011; 31 (11): 3981-3989

  Abstract

  Injury and inflammation are potent regulators of adult neurogenesis. As the complement system forms a key immune pathway that may also exert critical functions in neural development and neurodegeneration, we asked whether complement receptors regulate neurogenesis. We discovered that complement receptor 2 (CR2), classically known as a coreceptor of the B-lymphocyte antigen receptor, is expressed in adult neural progenitor cells (NPCs) of the dentate gyrus. Two of its ligands, C3d and interferon-α (IFN-α), inhibited proliferation of wild-type NPCs but not NPCs derived from mice lacking Cr2 (Cr2(-/-)), indicating functional Cr2 expression. Young and old Cr2(-/-) mice exhibited prominent increases in basal neurogenesis compared with wild-type littermates, whereas intracerebral injection of C3d resulted in fewer proliferating neuroblasts in wild-type than in Cr2(-/-) mice. We conclude that Cr2 regulates hippocampal neurogenesis and propose that increased C3d and IFN-α production associated with brain injury or viral infections may inhibit neurogenesis.

  View details for DOI 10.1523/JNEUROSCI.3617-10.2011

  View details for Web of Science ID 000288455700008

  View details for PubMedID 21411641

  View details for PubMedCentralID PMC3071463

• Workshop Summary: Roles of the TNF Family in Neuronal Development, Function and Pathology 12th Biennial International Tumor Necrosis Factor Conference Tansey, M. G., Wyss-Coray, T. SPRINGER-VERLAG BERLIN. 2011: 537–538

  View details for DOI 10.1007/978-1-4419-6612-4_55

  View details for Web of Science ID 000291501300057

  View details for PubMedID 21153358

• Beclin 1 Complex in Autophagy and Alzheimer Disease ARCHIVES OF NEUROLOGY Jaeger, P. A., Wyss-Coray, T. 2010; 67 (10): 1181-1184

  Abstract

  Beclin 1 is a protein involved in the regulation of autophagy and has been shown to be reduced in patients with Alzheimer disease. This review summarizes the current research data that link disturbances in autophagy, a cellular degradation and maintenance pathway, to the development of Alzheimer disease and related neurodegenerative diseases. It also provides a brief overview of the existing pharmacological interventions available to modulate autophagy activity in mammalian cells.

  View details for Web of Science ID 000282766300003

  View details for PubMedID 20937944

• Cellular Source of Apolipoprotein E4 Determines Neuronal Susceptibility to Excitotoxic Injury in Transgenic Mice AMERICAN JOURNAL OF PATHOLOGY Buttini, M., Masliah, E., Yu, G., Palop, J. J., Chang, S., Bernardo, A., Lin, C., Wyss-Coray, T., Huang, Y., Mucke, L. 2010; 177 (2): 563-569

  Abstract

  The lipid transport protein apolipoprotein E (apoE) is abundantly expressed in the brain. Its main isoforms in humans are apoE2, apoE3, and apoE4. ApoE4 is the major known genetic risk factor for Alzheimer's disease and also contributes to the pathogenesis of various other neurological conditions. In the central nervous system, apoE is synthesized by glial cells and neurons, but it is unclear whether the cellular source affects its biological activities. To address this issue, we induced excitotoxic injury by systemic kainic acid injection in transgenic Apoe knockout mice expressing human apoE isoforms in astrocytes or neurons. Regardless of its cellular source, apoE3 expression protected neuronal synapses and dendrites against the excitotoxicity seen in apoE-deficient mice. Astrocyte-derived apoE4, which has previously been shown to have detrimental effects in vitro, was as excitoprotective as apoE3 in vivo. In contrast, neuronal expression of apoE4 was not protective and resulted in loss of cortical neurons after excitotoxic challenge, indicating that neuronal apoE4 promotes excitotoxic cell death. Thus, an imbalance between astrocytic (excitoprotective) and neuronal (neurotoxic) apoE4 expression may increase susceptibility to diverse neurological diseases involving excitotoxic mechanisms.

  View details for DOI 10.2353/ajpath.2010.090973

  View details for Web of Science ID 000280894600008

  View details for PubMedID 20595630

• Angiotensin II sustains brain inflammation in mice via TGF-beta JOURNAL OF CLINICAL INVESTIGATION Lanz, T. V., Ding, Z., Ho, P. P., Luo, J., Agrawal, A. N., Srinagesh, H., Axtell, R., Zhang, H., Platten, M., Wyss-Coray, T., Steinman, L. 2010; 120 (8): 2782-2794

  Abstract

  The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease. Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-beta. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE. In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-beta expression via a pathway involving the TGF-beta-activating protease thrombospondin-1 (TSP-1). TGF-beta upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R. Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1. These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

  View details for DOI 10.1172/JCI41709

  View details for Web of Science ID 000280492100015

  View details for PubMedID 20628203

  View details for PubMedCentralID PMC2912186

• Regulation of Amyloid Precursor Protein Processing by the Beclin 1 Complex PLOS ONE Jaeger, P. A., Pickford, F., Sun, C., Lucin, K. M., Masliah, E., Wyss-Coray, T. 2010; 5 (6)

  Abstract

  Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex containing Beclin 1 (BECN1) and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3). Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD). However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP) and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF) are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3). Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.

  View details for DOI 10.1371/journal.pone.0011102

  View details for Web of Science ID 000278775900004

  View details for PubMedID 20559548

  View details for PubMedCentralID PMC2886067

• Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in alpha-Synuclein Models of Parkinson's and Lewy Body Diseases JOURNAL OF NEUROSCIENCE Spencer, B., Potkar, R., Trejo, M., Rockenstein, E., Patrick, C., Gindi, R., Adame, A., Wyss-Coray, T., Masliah, E. 2009; 29 (43): 13578-13588

  Abstract

  Accumulation of the synaptic protein alpha-synuclein (alpha-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD), a heterogeneous group of disorders with dementia and parkinsonism, where Alzheimer's disease and PD interact. Accumulation of alpha-syn in these patients might be associated with alterations in the autophagy pathway. Therefore, we postulate that delivery of beclin 1, a regulator of the autophagy pathway, might constitute a strategy toward developing a therapy for LBD/PD. Overexpression of alpha-syn from lentivirus transduction in a neuronal cell line resulted in lysosomal accumulation and alterations in autophagy. Coexpression of beclin 1 activated autophagy, reduced accumulation of alpha-syn, and ameliorated associated neuritic alterations. The effects of beclin 1 overexpression on LC3 and alpha-syn accumulation were partially blocked by 3-MA and completely blocked by bafilomycin A1. In contrast, rapamycin enhanced the effects of beclin 1. To evaluate the potential effects of activating autophagy in vivo, a lentivirus expressing beclin 1 was delivered to the brain of a alpha-syn transgenic mouse. Neuropathological analysis demonstrated that beclin 1 injections ameliorated the synaptic and dendritic pathology in the tg mice and reduced the accumulation of alpha-syn in the limbic system without any significant deleterious effects. This was accompanied by enhanced lysosomal activation and reduced alterations in the autophagy pathway. Thus, beclin 1 plays an important role in the intracellular degradation of alpha-syn either directly or indirectly through the autophagy pathway and may present a novel therapeutic target for LBD/PD.

  View details for DOI 10.1523/JNEUROSCI.4390-09.2009

  View details for Web of Science ID 000271266600017

  View details for PubMedID 19864570

• Immune Activation in Brain Aging and Neurodegeneration: Too Much or Too Little? NEURON Lucin, K. M., Wyss-Coray, T. 2009; 64 (1): 110-122

  Abstract

  Until recently, the brain was studied almost exclusively by neuroscientists and the immune system by immunologists, fuelling the notion that these systems represented two isolated entities. However, as more data suggest an important role of the immune system in regulating the progression of brain aging and neurodegenerative disease, it has become clear that the crosstalk between these systems can no longer be ignored and a new interdisciplinary approach is necessary. A central question that emerges is whether immune and inflammatory pathways become hyperactivated with age and promote degeneration or whether insufficient immune responses, which fail to cope with age-related stress, may contribute to disease. We try to explore here the consequences of gain versus loss of function with an emphasis on microglia as sensors and effectors of immune function in the brain, and we discuss the potential role of the peripheral environment in neurodegenerative diseases.

  View details for DOI 10.1016/j.neuron.2009.08.039

  View details for Web of Science ID 000271454400015

  View details for PubMedID 19840553

  View details for PubMedCentralID PMC2834890

• The p75 Neurotrophin Receptor Promotes Amyloid-beta(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo JOURNAL OF NEUROSCIENCE Knowles, J. K., Rajadas, J., Nguyen, T. V., Yang, T., LeMieux, M. C., Griend, L. V., Ishikawa, C., Massa, S. M., Wyss-Coray, T., Longo, F. M. 2009; 29 (34): 10627-10637

  Abstract

  Oligomeric forms of amyloid-beta (Abeta) are thought to play a causal role in Alzheimer's disease (AD), and the p75 neurotrophin receptor (p75(NTR)) has been implicated in Abeta-induced neurodegeneration. To further define the functions of p75(NTR) in AD, we examined the interaction of oligomeric Abeta(1-42) with p75(NTR), and the effects of that interaction on neurite integrity in neuron cultures and in a chronic AD mouse model. Atomic force microscopy was used to ascertain the aggregated state of Abeta, and fluorescence resonance energy transfer analysis revealed that Abeta oligomers interact with the extracellular domain of p75(NTR). In vitro studies of Abeta-induced death in neuron cultures isolated from wild-type and p75(NTR-/-) mice, in which the p75(NTR) extracellular domain is deleted, showed reduced sensitivity of mutant cells to Abeta-induced cell death. Interestingly, Abeta-induced neuritic dystrophy and activation of c-Jun, a known mediator of Abeta-induced deleterious signaling, were completely prevented in p75(NTR-/-) neuron cultures. Thy1-hAPP(Lond/Swe) x p75(NTR-/-) mice exhibited significantly diminished hippocampal neuritic dystrophy and complete reversal of basal forebrain cholinergic neurite degeneration relative to those expressing wild-type p75(NTR). Abeta levels were not affected, suggesting that removal of p75(NTR) extracellular domain reduced the ability of excess Abeta to promote neuritic degeneration. These findings indicate that although p75(NTR) likely does not mediate all Abeta effects, it does play a significant role in enabling Abeta-induced neurodegeneration in vitro and in vivo, establishing p75(NTR) as an important therapeutic target for AD.

  View details for DOI 10.1523/JNEUROSCI.0620-09.2009

  View details for PubMedID 19710315

• Bioactive TGF-beta can associate with lipoproteins and is enriched in those containing apolipoprotein E3 JOURNAL OF NEUROCHEMISTRY Tesseur, I., Zhang, H., Brecht, W., Corn, J., Gong, J., Yanagisawa, K., Michikawa, M., Weisgraber, K., Huang, Y., Wyss-Coray, T. 2009; 110 (4): 1254-1262

  Abstract

  Transforming growth factor-beta1 (TGF-beta1) has central functions in development, tissue maintenance, and repair and has been implicated in major diseases. We discovered that TGF-beta1 contains several amphipathic helices and hydrophobic domains similar to apolipoprotein E (apoE), a protein involved in lipoprotein metabolism. Indeed, TGF-beta1 associates with lipoproteins isolated from human plasma, cultured liver cells, or astrocytes, and its bioactivity was highest in high-density lipoprotein preparations. Importantly, lipoproteins containing the apoE3 isoform had higher TGF-beta levels and bioactivity than those containing apoE4, a major genetic risk factor for atherosclerosis and Alzheimer's disease. Because TGF-beta1 can be protective in these diseases an association with apoE3 may be beneficial. Association of TGF-beta with different types of lipoproteins may facilitate its diffusion, regulate signaling, and offer additional specificity for this important growth factor.

  View details for DOI 10.1111/j.1471-4159.2009.06222.x

  View details for Web of Science ID 000268221500011

  View details for PubMedID 19549280

  View details for PubMedCentralID PMC2915937

• Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Britschgi, M., Olin, C. E., Johns, H. T., Takeda-Uchimura, Y., LeMieux, M. C., Rufibach, K., Rajadas, J., Zhang, H., Tomooka, B., Robinson, W. H., Clark, C. M., Fagan, A. M., Galasko, D. R., Holtzman, D. M., Jutel, M., Kaye, J. A., Lemere, C. A., Leszek, J., Li, G., Peskind, E. R., Quinn, J. F., Yesavage, J. A., Ghiso, J. A., Wyss-Coray, T. 2009; 106 (29): 12145-12150

  Abstract

  A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

  View details for DOI 10.1073/pnas.0904866106

  View details for Web of Science ID 000268178400059

  View details for PubMedID 19581601

  View details for PubMedCentralID PMC2715538

• Blood Protein Signature for the Early Diagnosis of Alzheimer Disease ARCHIVES OF NEUROLOGY Britschgi, M., Wyss-Coray, T. 2009; 66 (2): 161-165

  Abstract

  Alzheimer disease (AD) has become one of the main health concerns for the elderly population in the United States. Current treatments target symptoms only, but several advanced clinical trials are testing new drugs that are potentially disease modifying. Because AD is still difficult to diagnose in its earliest stages and the disease process is estimated to start many years before current clinical diagnosis is made, accurate and simple diagnostic tools are urgently needed. We recently described a blood-based panel of secreted signaling proteins that distinguishes between blinded samples from patients with AD and control subjects with high accuracy. The same proteins also predicted progression to AD in preclinical patients with mild cognitive impairment several years before clinical diagnosis for AD was made. Herein, we describe these findings and discuss the potential for a more general application of our proteomic approach in understanding and diagnosing disease.

  View details for Web of Science ID 000263203200003

  View details for PubMedID 19064741

• Bioluminescence analysis of Smad-dependent TGF-beta signaling in live mice. Methods in molecular biology (Clifton, N.J.) Luo, J., Wyss-Coray, T. 2009; 574: 193-202

  Abstract

  TGF-beta signaling via the Smad2/3 pathway has key roles in development and tissue homeostasis. Perturbations of the TGF-beta signaling are involved in the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in living animals, we engineered transgenic mice with a Smad-responsive luciferase reporter (SBE-luc mice). Smad2/3-dependent signaling can be assessed non-invasively in living mice by bioluminescence imaging. To identify the cellular source of the bioluminescence signal, we generated new reporter mice expressing a trifusion protein containing luciferase, red fluorescent protein (RFP), and thymidine kinase under the control of the same SBE promoter (SBE-lucRT mice). SBE-luc and SBE-lucRT mice can be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice as well as for the identification of endogenous or synthetic modulators of this pathway.

  View details for DOI 10.1007/978-1-60327-321-3_16

  View details for PubMedID 19685310

• TGF beta signaling in immune mediated CNS disease Wyss-Coray, T., Ding, Z., Luo, J. ELSEVIER SCIENCE BV. 2008: 205–

  View details for Web of Science ID 000261270600218

• Microglia - A wrench in the running wheel? NEURON Villeda, S., Wyss-Coray, T. 2008; 59 (4): 527-529

  Abstract

  Increasing the amount of physical activity has been observed to ameliorate the progression of Alzheimer's disease (AD), as well as enhance neurogenesis. Choi et al. in this issue of Neuron report that the expression of Presenilin 1 (PS1) variants, responsible for the early onset of familial AD, are capable of mitigating the regenerative effects associated with increased activity and environmental enrichment likely through changes in resident microglia and their secreted factors.

  View details for DOI 10.1016/j.neuron.2008.08.005

  View details for PubMedID 18760689

• Genes contributing to prion pathogenesis JOURNAL OF GENERAL VIROLOGY Tamguney, G., Giles, K., Glidden, D. V., Lessard, P., Wille, H., Tremblay, P., Groth, D. F., Yehiely, F., Korth, C., Moore, R. C., Tatzelt, J., Rubinstein, E., Boucheix, C., Yang, X., Stanley, P., Lisanti, M. P., Dwek, R. A., Rudd, P. M., Moskovitz, J., Epstein, C. J., Cruz, T. D., Kuziel, W. A., Maeda, N., Sap, J., Ashe, K. H., Carlson, G. A., Tesseur, I., Wyss-Coray, T., Mucke, L., Weisgraber, K. H., Mahley, R. W., Cohen, F. E., Prusiner, S. B. 2008; 89: 1777-1788

  Abstract

  Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

  View details for DOI 10.1099/vir.0.2008/001255-0

  View details for Web of Science ID 000257554600026

  View details for PubMedID 18559949

  View details for PubMedCentralID PMC2828448

• The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice JOURNAL OF CLINICAL INVESTIGATION Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B., Wyss-Coray, T. 2008; 118 (6): 2190-2199

  Abstract

  Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.

  View details for DOI 10.1172/JCI33585

  View details for Web of Science ID 000256445100023

  View details for PubMedID 18497889

  View details for PubMedCentralID PMC2391284

• Bioluminescence in vivo imaging of autoimmune encephalomyelitis predicts disease JOURNAL OF NEUROINFLAMMATION Luo, J., Ho, P., Steinman, L., Wyss-Coray, T. 2008; 5

  Abstract

  Experimental autoimmune encephalomyelitis is a widely used animal model to understand not only multiple sclerosis but also basic principles of immunity. The disease is scored typically by observing signs of paralysis, which do not always correspond with pathological changes.Experimental autoimmune encephalomyelitis was induced in transgenic mice expressing an injury responsive luciferase reporter in astrocytes (GFAP-luc). Bioluminescence in the brain and spinal cord was measured non-invasively in living mice. Mice were sacrificed at different time points to evaluate clinical and pathological changes. The correlation between bioluminescence and clinical and pathological EAE was statistically analyzed by Pearson correlation analysis.Bioluminescence from the brain and spinal cord correlates strongly with severity of clinical disease and a number of pathological changes in the brain in EAE. Bioluminescence at early time points also predicts severity of disease.These results highlight the potential use of bioluminescence imaging to monitor neuroinflammation for rapid drug screening and immunological studies in EAE and suggest that similar approaches could be applied to other animal models of autoimmune and inflammatory disorders.

  View details for DOI 10.1186/1742-2094-5-6

  View details for Web of Science ID 000254547500001

  View details for PubMedID 18237444

  View details for PubMedCentralID PMC2267451

• Real-time Imaging of molecular signaling after stroke - Novel reporter mice for dissection of in vivo responses to TGF-beta 33rd International Stroke Conference Buckwalter, M. S., Luo, J., Debsi, B., Wyss-Coray, T. LIPPINCOTT WILLIAMS & WILKINS. 2008: 659–59

  View details for Web of Science ID 000252726100580

• Bioluminescent imaging of excitotoxic and endotoxic brain injury in living mice 7th International Conference on Progress in Alzheimers and Parkinsons Disease Luo, J., Lin, A. H., Wyss-Coray, T. SPRINGER. 2008: 175–182

  View details for Web of Science ID 000255426400017

• Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis JOURNAL OF CLINICAL INVESTIGATION Luo, J., Ho, P. P., Buckwalter, M. S., Hsu, T., Lee, L. Y., Zhang, H., Kim, D., Kim, S., Gambhir, S. S., Steinman, L., Wyss-Coray, T. 2007; 117 (11): 3306-3315

  Abstract

  Autoimmune encephalomyelitis, a mouse model for multiple sclerosis, is characterized by the activation of immune cells, demyelination of axons in the CNS, and paralysis. We found that TGF-beta1 synthesis in glial cells and TGF-beta-induced signaling in the CNS were activated several days before the onset of paralysis in mice with autoimmune encephalomyelitis. While early production of TGF-beta1 was observed in glial cells TGF-beta signaling was activated in neurons and later in infiltrating T cells in inflammatory lesions. Systemic treatment with a pharmacological inhibitor of TGF-beta signaling ameliorated the paralytic disease and reduced the accumulation of pathogenic T cells and expression of IL-6 in the CNS. Priming of peripheral T cells was not altered, nor was the generation of TH17 cells, indicating that this effect was directed within the brain, yet affected the immune system. These results suggest that early production of TGF-beta1 in the CNS creates a permissive and dangerous environment for the initiation of autoimmune inflammation, providing a rare example of the brain modulating the immune system. Importantly, inhibition of TGF-beta signaling may have benefits in the treatment of the acute phase of autoimmune CNS inflammation.

  View details for DOI 10.1172/JCI31763

  View details for PubMedID 17965773

• Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins NATURE MEDICINE Ray, S., Britschgi, M., Herbert, C., Takeda-Uchimura, Y., Boxer, A., Blennow, K., Friedman, L. F., Galasko, D. R., Jutel, M., Karydas, A., Kaye, J. A., Leszek, J., Miller, B. L., Minthon, L., Quinn, J. F., Rabinovici, G. D., Robinson, W. H., Sabbagh, M. N., So, Y. T., Sparks, D. L., Tabaton, M., Tinklenberg, J., Yesavage, J. A., Tibshirani, R., Wyss-Coray, T. 2007; 13 (11): 1359-1362

  Abstract

  A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

  View details for DOI 10.1038/nm1653

  View details for Web of Science ID 000250736900029

  View details for PubMedID 17934472

• Orally administered TGF-beta is biologically active in the intestinal mucosa and enhances oral tolerance JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Ando, T., Hatsushika, K., Wako, M., Ohba, T., Koyama, K., Ohnuma, Y., Katoh, R., Ogawa, H., Okumura, K., Luo, J., Wyss-Coray, T., Nakao, A. 2007; 120 (4): 916-923

  Abstract

  Epidemiologic studies suggest that TGF-beta in breast milk provides protection against allergic disease during infancy. However, it is unclear whether orally administered TGF-beta, such as TGF-beta in human milk, retains and exerts its activity in the intestinal mucosa and can affect immune response (tolerance) to dietary antigens.We sought to determine whether orally administered TGF-beta is biologically active in intestinal mucosa and affects oral tolerance.Activity of orally administered TGF-beta in the intestinal mucosa was evaluated by means of in vivo imaging with transgenic mice expressing a Smad-responsive reporter construct (SBE-luc mice), by means of immunohistochemical staining with anti-phosphorylated Smad2 antibody, and by means of real-time RT-PCR analysis of TGF-beta and Smad7 mRNA expression. The effects of orally administered TGF-beta on oral tolerance induction were assessed in mice tolerized by means of high-dose ovalbumin (OVA) feeding.The oral administration of TGF-beta increased Smad-responsive reporter activity in the intestines of SBE-luc mice and induced Smad2 phosphorylation and TGF-beta and Smad7 mRNA expression in the intestines of BALB/c mice. Serum TGF-beta levels were also increased after oral administration of TGF-beta. BALB/c mice treated orally with OVA and TGF-beta showed augmented reduction of OVA-specific IgE and IgG1 antibodies, T-cell reactivity, and immediate-type skin reactions when compared with the mice treated orally with OVA alone.Orally administered TGF-beta retains sufficient biologic activity in intestinal mucosa and enhances oral tolerance.Oral administration of TGF-beta might become a potential strategy to prevent allergic diseases, such as food allergy.

  View details for DOI 10.1016/j.jaci.2007.05.023

  View details for Web of Science ID 000250157700028

  View details for PubMedID 17606291

• Live imaging of Smad2/3 signaling in mouse skin wound healing WOUND REPAIR AND REGENERATION Chong, A. K., Satterwhite, T., Pham, H. M., Costa, M. A., Luo, J., Longaker, M. T., Wyss-Coray, T., Chang, J. 2007; 15 (5): 762-766

  Abstract

  Biophotonics and real-time imaging are novel technologies that can greatly enhance the study of complex biological processes. We applied this technology in a transgenic mouse with a luciferase reporter gene fused to a transforming growth factor-beta (TGF-beta) responsive Smad2/3-binding element to study bioluminescence after skin wounding. Two dorsal midline excisional skin wounds were made using a biopsy punch. One wound was randomized to suture closure and the other allowed to heal by secondary intention (n=8 each wound). Bioluminescence was measured at fixed time points following surgery. Phospho-Smad2/3 immunohistochemistry was performed to localize expression in skin wound samples. In vivo bioluminescence increased following skin wounding. Peak activity occurred on day 17 and was fourfold that of baseline (p<0.05). Subgroup analysis of primary and secondary healing showed that primarily sutured wounds had peak activities earlier than those with secondary healing, although this did not reach statistical significance. Intense phospho-Smad2/3 staining was found in the hair follicles. In vivo bioluminescence tracks Smad2/3-dependent TGF-beta signaling in the in vivo wound healing process. Our findings suggest that signaling increases after wound healing, which contrasts with other studies that show raised TGF-beta signaling in the initial days following wounding.

  View details for DOI 10.1111/j.1524-475X.2007.00299.x

  View details for Web of Science ID 000249846800019

  View details for PubMedID 17971023

• Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells JOURNAL OF IMMUNOLOGY Matsumura, Y., Kobayashi, T., Ichiyama, K., Yoshida, R., Hashimoto, M., Takimoto, T., Tanaka, K., Chinen, T., Shichita, T., Wyss-Coray, T., Sato, K., Yoshimura, A. 2007; 179 (4): 2170-2179

  Abstract

  Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10(+) Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4(+) T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3(+) Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3(+) T cell-inducing tolerogenic DCs. SOCS3(-/-) DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3(-) effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3(+) Treg cells were selectively expanded by SOCS3(-/-) DCs. Adoptive transfer of SOCS3(-/-) DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3(+) T cell expansion was blocked by anti-TGF-beta Ab, and SOCS3(-/-) DCs produced higher levels of TGF-beta than WT-DCs, suggesting that TGF-beta plays an essential role in the expansion of Foxp3(+) Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.

  View details for Web of Science ID 000248959200019

  View details for PubMedID 17675476

• In vitro analysis of transforming growth factor-beta 1 inhibition in novel Transgenic SBE-luciferase mice ANNALS OF PLASTIC SURGERY Satterwhite, T. S., Chong, A. K., Luo, J., Pham, H., Costa, M., Longaker, M. T., Wyss-Coray, T., Chang, J. 2007; 59 (2): 207-213

  Abstract

  Transforming growth factor beta1 (TGF-beta1) expression correlates with scarring. A novel transgenic mouse model with a Smad2/3-responsive luciferase reporter construct (SBE-luc) has been developed. We hypothesized that bioluminescence in SBE-luc dermal fibroblasts could be measured to assess TGF-beta1 inhibition.Cultured dermal fibroblasts from SBE-luc mice were treated simultaneously with TGF-beta1 and increasing doses of either neutralizing antibody to TGF-beta (NA-TGFbeta) or SB-431542, a novel TGF-beta receptor kinase inhibitor. Fibroblasts were measured for luciferase activity. SBE-luc fibroblasts underwent Western blot analysis for collagen type I production.TGF-beta1 produced maximal luciferase activity in SBE-luc fibroblasts at 0.1 ng/mL (P < 0.05). NA-TGFbeta and SB-431542 inhibited luciferase activity in a dose-dependent fashion, with complete inhibition achieved by 0.1 microg/mL and 1 microM, respectively (P < 0.05). NA-TGFbeta and SB-431542 inhibited collagen type I production.Our in vitro results provide validation for further in vivo real-time imaging studies using the SBE-luc mouse as a novel wound-healing model.

  View details for DOI 10.1097/01.sap.0000252732.25168.34

  View details for Web of Science ID 000248363400017

  View details for PubMedID 17667417

• Immune cells may fend off Alzheimer disease NATURE MEDICINE Britschgi, M., Wyss-Coray, T. 2007; 13 (4): 408-409

  View details for Web of Science ID 000245543900015

  View details for PubMedID 17415372

• Systemic and acquired immune responses in alzheimer's disease 9th Workshop on Apoptosis in Biology and Medicine on Neuroinflammation in Neuronal Death and Repair Britschgi, M., Wyss-Coray, T. ELSEVIER ACADEMIC PRESS INC. 2007: 205–233

  Abstract

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by a progressive cognitive decline and dementia. AD brains are marked by amyloid plaques and neurofibrillary tangles, neuronal cell loss, and a prominent activation of glial cells, and innate immune responses. A growing number of studies in AD have also reported alterations in systemic immune responses including changes in lymphocyte and macrophage distribution and activation, the presence of autoantibodies, or abnormal cytokine production. Studies in animal models for AD support the notion that immune cells infiltrate the brain and may modulate the disease. Here we will review evidence for systemic alterations in immune responses and a role for acquired immunity in AD and discuss their potential contribution to the disease.

  View details for Web of Science ID 000248524100011

  View details for PubMedID 17678963

• A role for TGF-beta signaling in neurodegeneration: evidence from genetically engineered models. Current Alzheimer research Tesseur, I., Wyss-Coray, T. 2006; 3 (5): 505-513

  Abstract

  Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) afflict growing numbers of people but treatments are not available or ineffective. These diseases are characterized by the loss of specific neuronal populations, the accumulation of protein aggregates inside and sometimes outside neurons, and an activation of immune pathways in the brain. The causes of sporadic forms of AD or PD are not known but it has been postulated that reduced trophic support to neurons together with age dependent increases in cellular stress lead to chronic injury and ultimately the demise of neurons. TGF-betas are neuroprotective factors and organizers of injury responses and as such might have a role in neurodegenerative disease. We review here the evidence mostly from genetically manipulated mice that links the TGF-beta signaling pathway to neuronal phenotypes and neurodegeneration. Although many of these mutant models did not produce overt CNS phenotypes or adult brain were not studied due to embryonic lethality, there is growing support for a role of TGF-beta signaling in neuronal maintenance, function, and degeneration. Future studies will have to determine whether dysregulation of TGF-beta signaling in neurodegenerative diseases is significant and whether this signaling pathway may even be a target for treatment.

  View details for PubMedID 17168649

• Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Luo, J., Lin, A. H., Masliah, E., Wyss-Coray, T. 2006; 103 (48): 18326-18331

  Abstract

  The TGF-beta signaling pathway is a key organizer of injury and immune responses, and recent studies suggest it fulfills critical roles in CNS function and maintenance. TGF-beta receptor activation results in phosphorylation of Smad proteins, which subsequently translocate to the nucleus to regulate gene transcription by binding to Smad binding elements (SBE). Using SBE-luciferase reporter mice, we recently discovered that the brain has the highest Smad baseline activity of any major organ in the mouse, and we now demonstrate that this signal is primarily localized to pyramidal neurons of the hippocampus. In vivo excitatory stimulation with kainic acid (KA) resulted in an increase in luciferase activity and phosphorylated Smad2 (Smad2P), and nuclear translocation of Smad2P in hippocampal CA3 neurons correlated significantly with luciferase activity. Although this activation was most prominent at 24 h after KA administration in neurons, Smad2P immunoreactivity gradually increased in astrocytes and microglial cells at 3 and 5 days, consistent with reactive gliosis. Bioluminescence measured over the skull in living mice peaked at 12-72 h and correlated with the extent of microglial activation and pathological markers of neurodegeneration 5 days after injury. Treatment with the glutamate receptor antagonist MK-801 strongly reduced bioluminescence and pathology. These results show that Smad2 signaling is a sensitive marker of neuronal activation and CNS injury that can be used to monitor KA-induced neuronal degeneration. This and related mouse models may provide valuable tools to study mechanisms and treatments for neurodegeneration.

  View details for DOI 10.1073/pnas.0605077103

  View details for Web of Science ID 000242465200053

  View details for PubMedID 17110447

  View details for PubMedCentralID PMC1838750

• Increased T cell recruitment to the CNS after amyloid beta(1-42) immunization in Alzheimer's mice overproducing transforming growth factor-beta 1 JOURNAL OF NEUROSCIENCE Buckwalter, M. S., Coleman, B. S., Buttini, M., Barbour, R., Schenk, D., Games, D., Seubert, P., Wyss-Coray, T. 2006; 26 (44): 11437-11441

  Abstract

  Immunotherapy targeting the amyloid beta (Abeta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using Abeta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta1 overexpression in a mouse model for AD [amyloid precursor protein (APP) mice] leads to development of additional T cell infiltrates when mice were immunized at a young but not old age with AN1792. Notably, only mice overproducing both Abeta (APP mice) and TGF-beta1 experienced a rise in T lymphocyte number after immunization. One-third of infiltrating T cells were CD4 positive. We did not observe significant differences in B lymphocyte numbers in any of the genotypes or treatment groups. These results demonstrate that TGF-beta1 overproduction in the brain can promote T cell infiltration, in particular after Abeta(1-42) immunization. Likewise, levels of TGF-beta1 or other immune factors in brains of AD patients may influence the response to Abeta(1-42) immunization.

  View details for DOI 10.1523/JNEUROSCI.2436-06.2006

  View details for PubMedID 17079673

• Deficiency in neuronal TGF-beta signaling promotes neurodegeneratbn and Alzheimer's pathology JOURNAL OF CLINICAL INVESTIGATION Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Van Can, J., Lin, A. H., Crews, L., Tremblay, P., Mathews, P., Mucke, L., Masliah, E., Wyss-Coray, T. 2006; 116 (11): 3060-3069

  Abstract

  Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the beta-amyloid peptide (Abeta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (TbetaRII) is mainly expressed by neurons, and that TbetaRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted Abeta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted Abeta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.

  View details for DOI 10.1172/JCI27341

  View details for Web of Science ID 000241810900030

  View details for PubMedID 17080199

  View details for PubMedCentralID PMC1626127

• Inflammation in Alzheimer disease: driving force, bystander or beneficial response? NATURE MEDICINE Wyss-Coray, T. 2006; 12 (9): 1005-1015

  Abstract

  Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.

  View details for DOI 10.1038/nml1484

  View details for Web of Science ID 000240373900023

  View details for PubMedID 16960575

• Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's. Current Alzheimer research Wyss-Coray, T. 2006; 3 (3): 191-195

  Abstract

  Alzheimer's disease (AD) is a fatal neurodegenerative disease characterized by the loss of large numbers of forebrain neurons. There are currently no effective AD treatments available and the cause of the disease is unknown in the majority of cases. Because normal neuronal maintenance and survival depends on stimulation of key signaling pathways by a number of neurotrophic factors it has been postulated that reduced signaling by or expression of these factors may promote neurodegeneration. Growing evidence suggests that the transforming growth factor-beta (TGF-beta) signaling pathway may be one such neurotrophic pathway that meets important protective and survival roles in neurons. Here I explore this evidence and discuss the pathway as a potential target for the treatment of neurodegeneration and AD.

  View details for PubMedID 16842094

• Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases Symposium on Neuroprotective Strategies in Multiple Sclerosis Dhib-Jalbut, S., Arnold, D. L., Cleveland, D. W., Fisher, M., Friedlander, R. M., Mouradian, M. M., Przedborski, S., Trapp, B. D., Wyss-Coray, T., Yong, V. W. ELSEVIER SCIENCE BV. 2006: 198–215

  Abstract

  Multiple sclerosis is considered a disease of myelin destruction; Parkinson's disease (PD), one of dopaminergic neuron depletion; ALS, a disease of motor neuron death; and Alzheimer's, a disease of plaques and tangles. Although these disorders differ in important ways, they also have common pathogenic features, including inflammation, genetic mutations, inappropriate protein aggregates (e.g., Lewy bodies, amyloid plaques), and biochemical defects leading to apoptosis, such as oxidative stress and mitochondrial dysfunction. In most disorders, it remains uncertain whether inflammation and protein aggregation are neurotoxic or neuroprotective. Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies.

  View details for DOI 10.1016/j.jneuroim.2006.03.027

  View details for Web of Science ID 000240323300022

  View details for PubMedID 16983747

• Chronically increased transforming growth factor-beta 1 strongly inhibits hippocampal neurogenesis in aged mice AMERICAN JOURNAL OF PATHOLOGY Buckwalter, M. S., Yamane, M., Coleman, B. S., Ormerod, B. K., Chin, J. T., Palmer, T., Wyss-Coray, T. 2006; 169 (1): 154-164

  Abstract

  There is increasing evidence that hippocampal learning correlates strongly with neurogenesis in the adult brain. Increases in neurogenesis after brain injury also correlate with improved outcomes. With aging the capacity to generate new neurons decreases dramatically, both under normal conditions and after injury. How this decrease occurs is not fully understood, but we hypothesized that transforming growth factor (TGF)-beta1, a cell cycle regulator that rapidly increases after injury and with age, might play a role. We found that chronic overproduction of TGF-beta1 from astrocytes almost completely blocked the generation of new neurons in aged transgenic mice. Even young adult TGF-beta1 mice had 60% fewer immature, doublecortin-positive, hippocampal neurons than wild-type littermate controls. Bromodeoxyuridine labeling of dividing cells in 2-month-old TGF-beta1 mice confirmed this decrease in neuro-genesis and revealed a similar decrease in astrogenesis. Treatment of early neural progenitor cells with TGF-beta1 inhibited their proliferation. This strongly suggests that TGF-beta1 directly affects these cells before their differentiation into neurons and astrocytes. Together, these data show that TGF-beta1 is a potent inhibitor of hippocampal neural progenitor cell proliferation in adult mice and suggest that it plays a key role in limiting injury and age-related neurogenesis.

  View details for DOI 10.2353/ajpath.2006.051272

  View details for PubMedID 16816369

• Highly sensitive and specific bioassay for measuring bioactive TGF-beta BMC CELL BIOLOGY Tesseur, I., Zou, K., Berber, E., Zhang, H., Wyss-Coray, T. 2006; 7

  Abstract

  Transforming Growth Factor-beta (TGF-beta) regulates key biological processes during development and in adult tissues and has been implicated in many diseases. To study the biological functions of TGF-beta, sensitive, specific, and convenient bioassays are necessary. Here we describe a new cell-based bioassay that fulfills these requirements.Embryonic fibroblasts from Tgfb1-/- mice were stably transfected with a reporter plasmid consisting of TGF-beta responsive Smad-binding elements coupled to a secreted alkaline phosphatase reporter gene (SBE-SEAP). Clone MFB-F11 showed more than 1000-fold induction after stimulation with 1 ng/ml TGF-beta1, and detected as little as 1 pg/ml TGF-beta1. MFB-F11 cells were highly induced by TGF-beta1, TGF-beta2 and TGF-beta3, but did not show induction with related family members activin, nodal, BMP-2 and BMP-6 or with trophic factors bFGF and BDNF. MFB-F11 cells can detect and quantify TGF-beta in biological samples without prior enrichment of TGF-betas, and can detect biologically activated TGF-beta in a cell co-culture system.MFB-F11 cells can be used to rapidly and specifically measure TGF-beta with high sensitivity.

  View details for DOI 10.1186/1471-2121-7-15

  View details for Web of Science ID 000238363700001

  View details for PubMedID 16549026

  View details for PubMedCentralID PMC1479809

• Noninvasive bioluminescence imaging of neural injury and inflammation in mouse models 37th Annual Meeting of the American-Society-for-Neurochemistry Wyss-Coray, T., Luo, J. WILEY-BLACKWELL. 2006: 93–93

  View details for Web of Science ID 000235982900234

• Global analysis of Smad2/3-dependent TGF-beta signaling in living mice reveals prominent tissue-specific responses to injury JOURNAL OF IMMUNOLOGY Lin, A. H., Luo, J., Mondshein, L. H., ten Dijke, P., Vivien, D., Contag, C. H., Wyss-Coray, T. 2005; 175 (1): 547-554

  Abstract

  Smad2 and Smad3 (Smad2/3) proteins are key signaling molecules for TGF-beta and some related family members regulating the transcription of several hundred genes. TGF-beta have key roles in development, tissue homeostasis, and the pathogenesis of many human diseases, including cancer, fibrotic disorders, developmental defects, and neurodegeneration. To study the temporal and spatial patterns of Smad2/3-dependent signaling in normal and pathological conditions in the living organism, we engineered transgenic mice with a Smad-responsive luciferase reporter construct (SBE-luc mice). Using bioluminescent imaging, we assessed Smad2/3 signaling activity noninvasively in living mice. At baseline, this activity was highest in brain, intestine, heart, and skin, and correlated with biochemical measurements of reporter activity. Primary astrocytes cultured from SBE-luc mice showed specific activation of the reporter in response to Smad2/3-activating TGF-beta family members. Treatment of mice with the endotoxin LPS resulted in a fast and vigorous, but transient activation of the reporter in the intestine. Although the response was similarly rapid in brain, it remained increased, indicating important but different cellular responses to endotoxin challenge in these organs. Traumatic brain injury with a needle stab resulted in local activation of Smad2/3-dependent genes and a severalfold increase in bioluminescence in living mice. SBE-luc mice can therefore be used to study temporal, tissue-specific activation of Smad2/3-dependent signaling in living mice in normal or pathological conditions as well as for the identification of endogenous or synthetic modulators of this pathway.

  View details for Web of Science ID 000230050900069

  View details for PubMedID 15972691

• Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities NEUROBIOLOGY OF DISEASE Gaertner, R. F., Wyss-Coray, T., Von Euw, D., Lesne, S., Vivien, D., Lacombe, P. 2005; 19 (1-2): 38-46

  Abstract

  We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-beta1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-beta1 mice compared to non-transgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions. A highly significant inverse correlation was found between the density of thioflavin-S-positive blood vessels and blood flow in the hippocampus and the cortex. An inverse correlation was likewise found between meningeal staining and blood flow in thalamic nuclei and regions of high blood flow. Thus, the vascular abnormalities were associated locally with reduced perfusion rate and more widely with limitation in the blood flow. These chronic changes may be related to fibrillar and soluble A beta peptides, the amount of which was almost doubled in the brains of TGF-beta1 mice. Comparison with previous results of cerebral glucose utilization in TGF-beta1 mice shows that reduced utilization preferentially occurred in regions with a high metabolic rate and a relatively low blood flow, suggesting that the metabolic needs are not met by blood supply in these regions.

  View details for DOI 10.1016/j.nbd.2004.11.008

  View details for Web of Science ID 000228672900005

  View details for PubMedID 15837559

• Killing pain, killing neurons? NATURE MEDICINE Wyss-Coray, T. 2005; 11 (5): 472-473

  View details for DOI 10.1038/nm0505-472

  View details for Web of Science ID 000228915000013

  View details for PubMedID 15875048

• Small molecule tgf-beta mimetics as potential neuroprotective factors. Current Alzheimer research Zhang, H., Zou, K., Tesseur, I., Wyss-Coray, T. 2005; 2 (2): 183-186

  Abstract

  Neurodegenerative and dementing illnesses are becoming an increasing social and economical burden as the number of older people continues to grow in industrialized countries. Current knowledge of the processes leading to these diseases is still limited, and very few effective treatments are available. Because neurodegeneration is associated with an activation of injury and innate immune responses in the brain, drugs that could mimic the beneficial aspects of this response are potential therapeutic candidates. The cytokine transforming growth factor (TGF)-beta1 is an organizer of the brain's response to injury and is known to be neuroprotective. Previous studies from our lab also showed that TGF-beta1 can reduce accumulation of beta-amyloid peptide (Abeta), which appears to be central to Alzheimer's disease (AD) pathogenesis, and we therefore initiated a search for small molecule chemical compounds that could mimic this effect. We report here the identification of several such TGF-beta mimetics detected in an in vitro screen of a library with 5000 chemically diverse compounds. If active in vivo, these mimetics could be developed into candidates for the treatment of neurodegeneration.

  View details for PubMedID 15974916

• Modelling neuroinflammatory phenotypes in vivo. Journal of neuroinflammation Buckwalter, M. S., Wyss-Coray, T. 2004; 1 (1): 10

  Abstract

  Inflammation of the central nervous system is an important but poorly understood part of neurological disease. After acute brain injury or infection there is a complex inflammatory response that involves activation of microglia and astrocytes and increased production of cytokines, chemokines, acute phase proteins, and complement factors. Antibodies and T lymphocytes may be involved in the response as well. In neurodegenerative disease, where injury is more subtle but consistent, the inflammatory response is continuous. The purpose of this prolonged response is unclear, but it is likely that some of its components are beneficial and others are harmful. Animal models of neurological disease can be used to dissect the specific role of individual mediators of the inflammatory response and assess their potential benefit. To illustrate this approach, we discuss how mutant mice expressing different levels of the cytokine transforming growth factor beta-1 (TGF-beta1), a major modulator of inflammation, produce important neuroinflammatory phenotypes. We then demonstrate how crosses of TGF-beta1 mutant mice with mouse models of Alzheimer's disease (AD) produced important new information on the role of inflammation in AD and on the expression of different neuropathological phenotypes that characterize this disease.

  View details for DOI 10.1186/1742-2094-1-10

  View details for PubMedID 15285805

  View details for PubMedCentralID PMC500895

• Inhibition of the TGF-beta signaling pathway results in increased neurodegeneration and amyloid deposition in human APP transgenic mice 9th International Conference on Alzheimers Disease and Related Disorders Tesseur, I. C., Zou, K., Masliah, E., Corn, J., Brionne, T., Bard, F., Wyss-Coray, T. ELSEVIER SCIENCE INC. 2004: S154–S154

  View details for Web of Science ID 000223058700514

• Insights into the pathogenesis of hydrocephalus from transgenic and experimental animal models BRAIN PATHOLOGY Crews, L., Wyss-Coray, T., Masliah, E. 2004; 14 (3): 312-316

  Abstract

  Hydrocephalus is a progressive brain disorder characterized by abnormalities in the flow of cerebrospinal fluid (CSF) and ventricular dilatation that leads to cerebral atrophy, and if left untreated, can be fatal. Genetic mutations, congenital malformations, infectious diseases, intracerebral hemorrhages and tumors are common conditions resulting in hydrocephalus. Although the causes of obstructive hydrocephalus are better understood, the mechanisms resulting in chronic, progressive communicating congenital and acquired hydrocephalus are less well understood. In this regard, recent studies in transgenic (tg) mice suggest that increased expression of cytokines such as TGF-beta1 might play an important role by disrupting the vascular extracellular matrix (ECM) remodeling, promoting hemorrhages, and altering the reabsorption of CSF. In this context, the main objective of this manuscript is to provide an overview on the cellular and molecular mechanisms of hydrocephalus based on studies derived from tg and experimental animal models.

  View details for Web of Science ID 000223359400012

  View details for PubMedID 15446587

• Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice JOURNAL OF NEUROSCIENCE Brecht, W. J., Harris, F. M., Chang, S. J., Tesseur, I., Yu, G. Q., Xu, Q., Fish, J. D., Wyss-Coray, T., Buttini, M., Mucke, L., MAHLEY, R. W., Huang, Y. D. 2004; 24 (10): 2527-2534

  Abstract

  Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is unclear. Previously, we found C-terminal-truncated fragments of apoE in AD brains and showed that such fragments can cause neurodegeneration and can induce NFT-like inclusions in cultured neuronal cells and in transgenic mice. Here, we analyzed apoE fragmentation in brain tissue homogenates from transgenic mice expressing apoE3 or apoE4 in neurons [neuron-specific enolase (NSE)-apoE] or astrocytes [glial fibrillary acidic protein (GFAP)-apoE] by Western blotting. The C-terminal-truncated fragments of apoE accumulated, in an age-dependent manner, in the brains of NSE-apoE4 and, to a significantly lesser extent, NSE-apoE3 mice; however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 mice. In NSE-apoE mice, the pattern of apoE fragmentation resembled that seen in AD brains, and the fragmentation was specific for certain brain regions, occurring in the neocortex and hippocampus, which are vulnerable to AD-related neurodegeneration, but not in the less vulnerable cerebellum. Excitotoxic challenge with kainic acid significantly increased apoE fragmentation in NSE-apoE4 but not NSE-apoE3 mice. Phosphorylated tau (p-tau) also accumulated in an age-dependent manner in NSE-apoE4 mice and, to a much lesser extent, in NSE-apoE3 mice but not in GFAP-apoE3 or GFAP-apoE4 mice. Intraneuronal p-tau inclusions in the hippocampus were prominent in 21-month-old NSE-apoE4 mice but barely detectable in NSE-apoE3 mice. Thus, the accumulation of potentially pathogenic C-terminal-truncated fragments of apoE depends on both the isoform and the cellular source of apoE. Neuron-specific proteolytic cleavage of apoE4 is associated with increased phosphorylation of tau and may play a key role in the development of AD-related neuronal deficits.

  View details for DOI 10.1523/JNEUROSCI.4315-03.2004

  View details for Web of Science ID 000220129800020

  View details for PubMedID 15014128

• Astroglial regulation of apolipoprotein E expression in neuronal cells - Implications for Alzheimer's disease JOURNAL OF BIOLOGICAL CHEMISTRY Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S. J., Wyss-Coray, T., MAHLEY, R. W., Huang, Y. D. 2004; 279 (5): 3862-3868

  Abstract

  Although apolipoprotein (apo) E is synthesized in the brain primarily by astrocytes, neurons in the central nervous system express apoE, albeit at lower levels than astrocytes, in response to various physiological and pathological conditions, including excitotoxic stress. To investigate how apoE expression is regulated in neurons, we transfected Neuro-2a cells with a 17-kilobase human apoE genomic DNA construct encoding apoE3 or apoE4 along with upstream and downstream regulatory elements. The baseline expression of apoE was low. However, conditioned medium from an astrocytic cell line (C6) or from apoE-null mouse primary astrocytes increased the expression of both isoforms by 3-4-fold at the mRNA level and by 4-10-fold at the protein level. These findings suggest that astrocytes secrete a factor or factors that regulate apoE expression in neuronal cells. The increased expression of apoE was almost completely abolished by incubating neurons with U0126, an inhibitor of extracellular signal-regulated kinase (Erk), suggesting that the Erk pathway controls astroglial regulation of apoE expression in neuronal cells. Human neuronal precursor NT2/D1 cells expressed apoE constitutively; however, after treatment of these cells with retinoic acid to induce differentiation, apoE expression diminished. Cultured mouse primary cortical and hippocampal neurons also expressed low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in fully differentiated NT2 neurons and in cultured mouse primary cortical and hippocampal neurons. Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons.

  View details for DOI 10.1074/jbc.M309475200

  View details for Web of Science ID 000188379600088

  View details for PubMedID 14585838

• Transforming growth factor-beta signaling pathway as a therapeutic target in neurodegeneration JOURNAL OF MOLECULAR NEUROSCIENCE Wyss-Coray, T. 2004; 24 (1): 149-153

  Abstract

  Neurodegenerative diseases are becoming an increasing social and economical burden as our population ages; but current knowledge of the processes leading to these diseases is still limited, and no effective treatments are available. Neurodegeneration in Alzheimer's disease (AD) is the most common cause of dementia and afflicts an estimated 4 million people in this country alone. Because accumulation of beta-amyloid (Abeta) peptide appears central to AD pathogenesis, large efforts have been directed at understanding and interfering with Abeta production or aggregation. These efforts have largely identified the processes resulting in Abeta production from the larger amyloid precursor protein (APP) and have revealed that Abeta peptide is also produced at low levels in the healthy brain. Interestingly, Abeta production is rapidly increased after neuronal injury, and traumatic brain injury is a known risk factor for AD and Parkinson's disease. In contrast, brain injury in young individuals does not seem to result in AD, and brain injury in animal models can promote Abeta clearance. This suggests that certain factors associated with injury might be able to reduce the accumulation of Abeta. Accumulation of Abeta peptide might be reduced either directly by stimulating phagocytes or other Abeta-degrading processes, or indirectly, by reducing neuronal injury and thus lowering the production of Abeta peptide. Directing the brain's natural mechanisms for clearing Abeta or increasing neuroprotection might therefore be reasonable approaches in interfering with AD pathogenesis.

  View details for Web of Science ID 000223521700022

  View details for PubMedID 15314264

• Modelling neuroinflammatory phenotypes in vivo JOURNAL OF NEUROINFLAMMATION Buckwalter, M. S., Wyss-Coray, T. 2004; 1

  Abstract

  Inflammation of the central nervous system is an important but poorly understood part of neurological disease. After acute brain injury or infection there is a complex inflammatory response that involves activation of microglia and astrocytes and increased production of cytokines, chemokines, acute phase proteins, and complement factors. Antibodies and T lymphocytes may be involved in the response as well. In neurodegenerative disease, where injury is more subtle but consistent, the inflammatory response is continuous. The purpose of this prolonged response is unclear, but it is likely that some of its components are beneficial and others are harmful. Animal models of neurological disease can be used to dissect the specific role of individual mediators of the inflammatory response and assess their potential benefit. To illustrate this approach, we discuss how mutant mice expressing different levels of the cytokine transforming growth factor beta-1 (TGF-beta1), a major modulator of inflammation, produce important neuroinflammatory phenotypes. We then demonstrate how crosses of TGF-beta1 mutant mice with mouse models of Alzheimer's disease (AD) produced important new information on the role of inflammation in AD and on the expression of different neuropathological phenotypes that characterize this disease.

  View details for DOI 10.1186/1742-2094-1-10

  View details for Web of Science ID 000208759200010

  View details for PubMedCentralID PMC500895

• Loss of TGF-beta 1 leads to increased neuronal cell death and microgliosis in mouse brain NEURON Brionne, T. C., Tesseur, I., Masliah, E., Wyss-Coray, T. 2003; 40 (6): 1133-1145

  Abstract

  TGF-beta1 is a key regulator of diverse biological processes in many tissues and cell types, but its exact function in the developing and adult mammalian CNS is still unknown. We report that lack of TGF-beta1 expression in neonatal Tgfb1(-/-) mice results in a widespread increase in degenerating neurons accompanied by reduced expression of synaptophysin and laminin and a prominent microgliosis. Lack of TGF-beta1 also strongly reduces survival of primary neurons cultured from Tgfb1(-/-) mice. TGF-beta1 deficiency in adult Tgfb1(-/+) mice results in increased neuronal susceptibility to excitotoxic injury, whereas astroglial overexpression of TGF-beta1 protects adult mice against neurodegeneration in acute, excitotoxic and chronic injury paradigms. This study reveals a nonredundant function for TGF-beta1 in maintaining neuronal integrity and survival of CNS neurons and in regulating microglial activation. Because individual TGF-beta1 expression levels in the brain vary considerably between humans, this finding could have important implications for susceptibility to neurodegeneration.

  View details for Web of Science ID 000187503400012

  View details for PubMedID 14687548

• Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., Weisgraber, K. H., Mucke, L., MAHLEY, R. W., Huang, Y. D. 2003; 100 (19): 10966-10971

  Abstract

  Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminal-truncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxyl-terminal-cleaved product, apoE4(Delta272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silver-positive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6-7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits.

  View details for DOI 10.1073/pnas.1434398100

  View details for Web of Science ID 000185415300070

  View details for PubMedID 12939405

• Adult mouse astrocytes degrade amyloid-beta in vitro and in situ NATURE MEDICINE Wyss-Coray, T., Loike, J. D., Brionne, T. C., Lu, E., Anankov, R., Yan, F. R., Silverstein, S. C., Husemann, J. 2003; 9 (4): 453-457

  Abstract

  Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.

  View details for DOI 10.1038/nm838

  View details for Web of Science ID 000181987400036

  View details for PubMedID 12612547

• Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Wyss-Coray, T., Yan, F. R., Lin, A. H., Lambris, J. D., Alexander, J. J., Quigg, R. J., Masliah, E. 2002; 99 (16): 10837-10842

  Abstract

  Abnormal accumulation of beta-amyloid (Abeta) in Alzheimer's disease (AD) is associated with prominent brain inflammation. Whereas earlier studies concluded that this inflammation is detrimental, more recent animal data suggest that at least some inflammatory processes may be beneficial and promote Abeta clearance. Consistent with these observations, overproduction of transforming growth factor (TGF)-beta1 resulted in a vigorous microglial activation that was accompanied by at least a 50% reduction in Abeta accumulation in human amyloid precursor protein (hAPP) transgenic mice. In a search for inflammatory mediators associated with this reduced pathology, we found that brain levels of C3, the central component of complement and a key inflammatory protein activated in AD, were markedly higher in hAPP/TGF-beta1 mice than in hAPP mice. To assess the importance of complement in the pathogenesis of AD-like disease in mice, we inhibited C3 activation by expressing soluble complement receptor-related protein y (sCrry), a complement inhibitor, in the brains of hAPP mice. Abeta deposition was 2- to 3-fold higher in 1-year-old hAPP/sCrry mice than in age-matched hAPP mice and was accompanied by a prominent accumulation of degenerating neurons. These results indicate that complement activation products can protect against Abeta-induced neurotoxicity and may reduce the accumulation or promote the clearance of amyloid and degenerating neurons. These findings provide evidence for a role of complement and innate immune responses in AD-like disease in mice and support the concept that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease.

  View details for DOI 10.1073/pnas.162350199

  View details for Web of Science ID 000177343200110

  View details for PubMedID 12119423

• Inflammation in neurodegenerative disease - A double-edged sword NEURON Wyss-Coray, T., Mucke, L. 2002; 35 (3): 419-432

  Abstract

  Inflammation is a defense reaction against diverse insults, designed to remove noxious agents and to inhibit their detrimental effects. It consists of a dazzling array of molecular and cellular mechanisms and an intricate network of controls to keep them in check. In neurodegenerative diseases, inflammation may be triggered by the accumulation of proteins with abnormal conformations or by signals emanating from injured neurons. Given the multiple functions of many inflammatory factors, it has been difficult to pinpoint their roles in specific (patho)physiological situations. Studies of genetically modified mice and of molecular pathways in activated glia are beginning to shed light on this issue. Altered expression of different inflammatory factors can either promote or counteract neurodegenerative processes. Since many inflammatory responses are beneficial, directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it.

  View details for Web of Science ID 000177331200005

  View details for PubMedID 12165466

• Molecular and functional dissection of TGF-beta 1-induced cerebrovascular abnormalities in transgenic mice 3rd World Congress on Vascular Factors in Alzheimers Disease Buckwalter, M., Pepper, J. P., Gaertner, R. F., Von Euw, D., Lacombe, P., Wyss-Coray, T. NEW YORK ACAD SCIENCES. 2002: 87–95

  Abstract

  Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S-positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-beta1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.

  View details for Web of Science ID 000179767000009

  View details for PubMedID 12480736

• Functional role of TGF beta in Alzheimer's disease microvascular injury: lessons from transgenic mice NEUROCHEMISTRY INTERNATIONAL Masliah, E., Ho, G., Wyss-Coray, T. 2001; 39 (5-6): 393-400

  Abstract

  Recent studies have implicated pro- and anti-inflammatory cytokines as integral to Alzheimer's disease (AD) pathogenesis. Among them, transforming growth factor-beta (TGF-beta) is emerging as an important factor in regulating inflammatory responses. This multifunctional cytokine might be centrally involved in several aspects of AD pathogenesis by regulating beta-amyloid precursor protein synthesis and processing, plaque formation, astroglial and microglial response and neuronal cell death. Among all of these potential roles, studies in transgenic and infusion animal models have shown that TGF-beta may primarily contribute to AD pathogenesis by influencing A beta production and deposition, which in turn might result in damage to the brain microvasculature. The lessons learned from these models are of great interest not only for understanding of the role of TGF-beta in AD, but also for future treatments where testing of anti-inflammatory agents such as ibuprofen and an amyloid vaccine hold great promise. In this regard, further elucidation of the signal pathways by which TGF-beta exerts its effect in AD might lead to specific targets for further therapeutic intervention.

  View details for Web of Science ID 000172052700008

  View details for PubMedID 11578774

• Key signaling pathways regulate the biological activities and accumulation of amyloid-beta NEUROBIOLOGY OF AGING Wyss-Coray, T., MCCONLOGUE, L., Kindy, M., Schmidt, A. M., Yan, S. D., Stern, D. M. 2001; 22 (6): 967-973

  View details for Web of Science ID 000173026100020

  View details for PubMedID 11755005

• Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Huang, Y. D., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., MAHLEY, R. W. 2001; 98 (15): 8838-8843

  Abstract

  Human apolipoprotein (apo) E4, a major risk factor for Alzheimer's disease (AD), occurs in amyloid plaques and neurofibrillary tangles (NFTs) in AD brains; however, its role in the pathogenesis of these lesions is unclear. Here we demonstrate that carboxyl-terminal-truncated forms of apoE, which occur in AD brains and cultured neurons, induce intracellular NFT-like inclusions in neurons. These cytosolic inclusions were composed of phosphorylated tau, phosphorylated neurofilaments of high molecular weight, and truncated apoE. Truncated apoE4, especially apoE4(Delta 272--299), induced inclusions in up to 75% of transfected neuronal cells, but not in transfected nonneuronal cells. ApoE4 was more susceptible to truncation than apoE3 and resulted in much greater intracellular inclusion formation. These results suggest that apoE4 preferentially undergoes intracellular processing, creating a bioactive fragment that interacts with cytoskeletal components and induces NFT-like inclusions containing phosphorylated tau and phosphorylated neurofilaments of high molecular weight in neurons.

  View details for Web of Science ID 000169967000112

  View details for PubMedID 11447277

• TGF-beta 1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice NATURE MEDICINE Wyss-Coray, T., Lin, C., Yan, F. R., Yu, G. Q., Rohde, M., MCCONLOGUE, L., Masliah, E., Mucke, L. 2001; 7 (5): 612-618

  Abstract

  Abnormal accumulation of the amyloid-beta peptide (Abeta) in the brain appears crucial to pathogenesis in all forms of Alzheimer disease (AD), but the underlying mechanisms in the sporadic forms of AD remain unknown. Transforming growth factor beta1 (TGF-beta1), a key regulator of the brain's responses to injury and inflammation, has been implicated in Abeta deposition in vivo. Here we demonstrate that a modest increase in astroglial TGF-beta1 production in aged transgenic mice expressing the human beta-amyloid precursor protein (hAPP) results in a three-fold reduction in the number of parenchymal amyloid plaques, a 50% reduction in the overall Abeta load in the hippocampus and neocortex, and a decrease in the number of dystrophic neurites. In mice expressing hAPP and TGF-beta1, Abeta accumulated substantially in cerebral blood vessels, but not in parenchymal plaques. In human cases of AD, Abeta immunoreactivity associated with parenchymal plaques was inversely correlated with Abeta in blood vessels and cortical TGF-beta1 mRNA levels. The reduction of parenchymal plaques in hAPP/TGF-beta1 mice was associated with a strong activation of microglia and an increase in inflammatory mediators. Recombinant TGF-beta1 stimulated Abeta clearance in microglial cell cultures. These results demonstrate that TGF-beta1 is an important modifier of amyloid deposition in vivo and indicate that TGF-beta1 might promote microglial processes that inhibit the accumulation of Abeta in the brain parenchyma.

  View details for Web of Science ID 000169961100042

  View details for PubMedID 11329064

• Ibuprofen, inflammation and Alzheimer disease NATURE MEDICINE Wyss-Coray, T., Mucke, L. 2000; 6 (9): 973-974

  View details for Web of Science ID 000089190500023

  View details for PubMedID 10973311

• Inflammation and Alzheimer's disease NEUROBIOLOGY OF AGING Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Cooper, N. R., Eikelenboom, P., Emmerling, M., Fiebich, B. L., Finch, C. E., Frautschy, S., Griffin, W. S., Hampel, H., Hull, M., Landreth, G., Lue, L. F., Mrak, R., Mackenzie, I. R., McGeer, P. L., O'Banion, M. K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., van Muiswinkel, F. L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., Wyss-Coray, T. 2000; 21 (3): 383-421

  Abstract

  Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.

  View details for Web of Science ID 000088059000001

  View details for PubMedID 10858586

• Chronic overproduction of transforming growth factor-beta 1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice AMERICAN JOURNAL OF PATHOLOGY Wyss-Coray, T., Lin, C., Sanan, D. A., Mucke, L., Masliah, E. 2000; 156 (1): 139-150

  Abstract

  Cerebrovascular amyloid deposition and microvascular degeneration are frequently associated with Alzheimer's disease (AD), but the etiology and pathogenetic role of these abnormalities are unknown. Recently, transforming growth factor-beta1 (TGF-beta1) was implicated in cerebrovascular amyloid formation in transgenic mice with astroglial overproduction of TGF-beta1 and in AD. We tested whether TGF-beta1 overproduction induces AD-like cerebrovascular degeneration and analyzed how cerebrovascular abnormalities develop over time in TGF-beta1-transgenic mice. In cerebral microvessels from 3- to 4-month-old TGF-beta1-transgenic mice, which display a prominent perivascular astrocytosis, levels of the basement membrane proteins perlecan and fibronectin were severalfold higher than in vessels from nontransgenic mice. Consistent with this increase, cortical capillary basement membranes of TGF-beta1 mice were significantly thickened. These changes preceded amyloid deposition, which began at around 6 months of age. In 9- and 18-month-old TGF-beta1 mice, various degenerative changes in microvascular cells of the brain were observed. Endothelial cells were thinner and displayed abnormal, microvilli-like protrusions as well as occasional condensation of chromatin, and pericytes occupied smaller areas in capillary profiles than in nontransgenic controls. Similar cerebrovascular abnormalities have been reported in AD. We conclude that chronic overproduction of TGF-beta1 triggers an accumulation of basement membrane proteins and results in AD-like cerebrovascular amyloidosis and microvascular degeneration. Closely related processes may induce cerebrovascular pathology in AD.

  View details for Web of Science ID 000084773300017

  View details for PubMedID 10623661

• Alzheimer's disease-like cerebrovascular pathology in transforming growth factor-beta 1 transgenic mice and functional metabolic correlates Conference on Vascular Factors in Alzheimers Disease Wyss-Coray, T., Lin, C., Von Euw, D., Masliah, E., Mucke, L., Lacombe, P. NEW YORK ACAD SCIENCES. 2000: 317–323

  Abstract

  Alzheimer's disease (AD) is frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. To characterize the temporal relationship between amyloid deposition, cerebrovascular abnormalities, and potential functional changes, we studied transgenic mice that express transforming growth factor-beta 1 (TGF-beta 1) at low levels in astrocytes. TGF-beta 1 induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. Associated with these morphological changes were changes in regional cerebral glucose utilization. Preliminary results showed that TGF-beta 1 mice had significantly decreased glucose utilization in the mammillary bodies, structures involved in mnemonic and learning processes. Glucose utilization tended to be decreased in several other brain regions as well; however, in the inferior colliculus, it was markedly higher in TGF-beta 1 mice than in controls. We conclude that chronic overproduction of TGF-beta 1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity. Similar mechanisms may be involved in AD pathogenesis.

  View details for Web of Science ID 000087756800041

  View details for PubMedID 10818521

• Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease NEUROSCIENCE Buttini, M., Akeefe, H., Lin, C., MAHLEY, R. W., Pitas, R. E., Wyss-Coray, T., Mucke, L. 2000; 97 (2): 207-210

  Abstract

  Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and neurodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimer's disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human apolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3. The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE varepsilon4 carriers.

  View details for Web of Science ID 000087064400001

  View details for PubMedID 10799751

• Elimination of the class a scavenger receptor does not affect amyloid plaque formation or neurodegeneration in transgenic mice expressing human amyloid protein precursors AMERICAN JOURNAL OF PATHOLOGY Huang, F., Buttini, M., Wyss-Coray, T., MCCONLOGUE, L., Kodama, T., Pitas, R. E., Mucke, L. 1999; 155 (5): 1741-1747

  Abstract

  The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.

  View details for Web of Science ID 000083587600039

  View details for PubMedID 10550330

• Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Xu, X., Yang, D. S., Wyss-Coray, T., Yan, J., Gan, L., Sun, Y., Mucke, L. 1999; 96 (13): 7547-7552

  Abstract

  Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abundance in brain and the association of various APP missense mutations with autosomal dominant forms of familial Alzheimer's disease (FAD) suggest important roles for APP in the central nervous system. However, the basic functions of APP in the central nervous system remain largely unknown. To assess potential effects of APP on neuronal death and survival, we transfected APP-deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild-type or FAD-mutant human APP. Wild-type, but not FAD-mutant, APP effectively protected cells against apoptosis induced by ultraviolet irradiation, staurosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, whereas FAD-mutant APP did not. We conclude that APP protects neuronal cells against apoptosis by controlling p53 activation at the post-translational level. Disruption of this function by mutations or alterations in APP processing could enhance neuronal vulnerability to secondary insults and contribute to neuronal degeneration.

  View details for Web of Science ID 000081056000078

  View details for PubMedID 10377452

• Expression of human apolipoprotein E3 or E4 in the brains of Apoe(-/-) mice: Isoform-specific effects on neurodegeneration JOURNAL OF NEUROSCIENCE Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss-Coray, T., Mucke, L., MAHLEY, R. W. 1999; 19 (12): 4867-4880

  Abstract

  Apolipoprotein (apo) E isoforms are key determinants of susceptibility to Alzheimer's disease. The apoE4 isoform is the major known genetic risk factor for this disease and is also associated with poor outcome after acute head trauma or stroke. To test the hypothesis that apoE3, but not apoE4, protects against age-related and excitotoxin-induced neurodegeneration, we analyzed apoE knockout (Apoe-/-) mice expressing similar levels of human apoE3 or apoE4 in the brain under control of the neuron-specific enolase promoter. Neuronal apoE expression was widespread in the brains of these mice. Kainic acid-challenged wild-type or Apoe-/- mice had a significant loss of synaptophysin-positive presynaptic terminals and microtubule-associated protein 2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus. Expression of apoE3, but not of apoE4, protected against this excitotoxin-induced neuronal damage. ApoE3, but not apoE4, also protected against the age-dependent neurodegeneration seen in Apoe-/- mice. These differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of Alzheimer's disease and to the poor outcome after head trauma and stroke associated with apoE4 in humans.

  View details for Web of Science ID 000080753800019

  View details for PubMedID 10366621

• Induction of matrix metalloproteinase-2 in human immunodeficiency virus-1 glycoprotein 120 transgenic mouse brains NEUROSCIENCE LETTERS Marshall, D. C., Wyss-Coray, T., Abraham, C. R. 1998; 254 (2): 97-100

  Abstract

  Human immunodeficiency virus (HIV)-1 can invade the brain and cause degeneration of the central nervous system, resulting in a host of cognitive and motor impairments. HIV-1 glycoprotein 120 (gp120), has been implicated in the neurodegenerative effects of HIV infection. Here, gp120's neurotoxic potential is demonstrated in both transgenic mice and cultured cells. We observed that gp120 causes an induction of matrix metalloproteinase (MMP)-2 activity and protein in transgenic mouse brains and in transfected C6 cells. We propose that induced MMP-2 may contribute to a neurodegenerative environment by degrading extracellular matrix (ECM) fibronectin and type IV collagen.

  View details for Web of Science ID 000076198300009

  View details for PubMedID 9779929

• Novel role of human CD4 molecule identified in neurodegeneration NATURE MEDICINE Buttini, M., Westland, C. E., Masliah, E., Yafeh, A. M., Wyss-Coray, T., Mucke, L. 1998; 4 (4): 441-446

  Abstract

  The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peripheral immune challenges elicited neurodegeneration in hCD4 mice but not in nontransgenic controls. In post-mortem brain tissues from AIDS patients with opportunistic infections, but without typical HIV encephalitis, hCD4 expression correlated with neurodegeneration. We conclude that hCD4 may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system.

  View details for Web of Science ID 000072906800039

  View details for PubMedID 9546790

• Amyloidogenic role of cytokine TGF-beta 1 in transgenic mice and in Alzheimer's disease NATURE WYSSCORAY, T., Masliah, E., Mallory, M., MCCONLOGUE, L., JOHNSONWOOD, K., Lin, C., Mucke, L. 1997; 389 (6651): 603-606

  Abstract

  Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.

  View details for Web of Science ID A1997YA00800060

  View details for PubMedID 9335500

• Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice JOURNAL OF NEUROIMMUNOLOGY WYSSCORAY, T., Borrow, P., Brooker, M. J., Mucke, L. 1997; 77 (1): 45-50

  Abstract

  Cerebral expression of the injury response cytokine transforming growth factor-beta 1 (TGF-beta 1) has been found to be increased in several neurological diseases but it remains unclear whether its function is primarily beneficial or detrimental. Here we show that transgenic (tg) mice that overexpress bioactive (TGF-beta 1 in the central nervous system (CNS) and show no overt phenotype in the unmanipulated state, are more susceptible to the immune-mediated CNS disease experimental autoimmune encephalomyelitis (EAE). TGF-beta 1 tg mice with EAE showed an earlier onset of clinical symptoms, more severe disease and increased mononuclear cell infiltration in their spinal cords compared with non-tg littermate controls with EAE. Whereas previous observations indicated that increased peripheral levels of TGF-beta 1 can suppress EAE, our findings demonstrate that local expression of TGF-beta 1 within the CNS parenchyma can enhance immune cell infiltration and intensify the CNS impairment resulting from peripherally triggered autoimmune responses.

  View details for Web of Science ID A1997XG79200006

  View details for PubMedID 9209267

• Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease BRAIN RESEARCH REVIEWS Mattson, M. P., Barger, S. W., Furukawa, K., Bruce, A. J., WYSSCORAY, T., Mark, R. J., Mucke, L. 1997; 23 (1-2): 47-61

  Abstract

  beta-Amyloid precursor protein (beta APP), transforming growth factor beta (TGF beta), and tumor necrosis factor-alpha (TNF alpha) are remarkably pleiotropic neural cytokines/neurotrophic factors that orchestrate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their association with cytopathological alterations in Alzheimer's disease. Astrocytes and microglia each produce and respond to TGF beta and TNF alpha in characteristic ways when the brain is injured. TGF beta, TNF alpha and secreted forms of beta APP (sAPP) can protect neurons against excitotoxic, metabolic and oxidative insults and may thereby serve neuroprotective roles. On the other hand, under certain conditions TNF alpha and the fibrillogenic amyloid beta-peptide (A beta) derivative of beta APP can promote damage of neuronal and glial cells, and may play roles in neurodegenerative disorders. Studies of genetically manipulated mice in which TGF beta, TNF alpha or beta APP ligand or receptor levels are altered suggest important roles for each factor in cellular responses to brain injury and indicate that mediators of neural injury responses also have the potential to enhance amyloidogenesis and/or to interfere with neuroregeneration if expressed at abnormal levels or modified by strategic point mutations. Recent studies have elucidated signal transduction pathways of TGF beta (serine/threonine kinase cascades), TNF alpha (p55 receptor linked to a sphingomyelin-ceramide-NF kappa B pathway), and secreted forms of beta APP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge of these signaling pathways is revealing novel molecular targets on which to focus neuroprotective therapeutic strategies in disorders ranging from stroke to Alzheimer's disease.

  View details for Web of Science ID A1997WN18500003

  View details for PubMedID 9063586

• Dysregulation of signal transduction pathways as a potential mechanism of nervous system alterations in HIV-1 gp 120 transgenic mice and humans with HIV-1 encephalitis JOURNAL OF CLINICAL INVESTIGATION WYSSCORAY, T., Masliah, E., Toggas, S. M., Rockenstein, E. M., Brooker, M. J., Lee, H. S., Mucke, L. 1996; 97 (3): 789-798

  Abstract

  HIV-1 associated central nervous system (CNS) disease involves neuronal damage and prominent reactive astrocytosis, the latter characterized by strong upregulation of the glial fibrillary acidic protein (GFAP) in astrocytes. Similar alterations are found in transgenic mice expressing the HIV-1 envelope protein gp120 in the CNS. Because alterations of astrocyte functions could contribute to neuronal impairment, we compared brains of gp120 transgenic mice and gp120-transfected C6 astrocytoma cells with controls and found that gp120 induced a prominent elevation of steady state GFAP mRNA levels, primarily due to transcript stabilization. Increased levels of GFAP mRNA were also found in nontransfected C6 cells exposed to recombinant gp120. Exposure of C6 cells or primary mouse astrocytes to soluble gp120 led to activation of PKC as indicated by redistribution and increase in PKC immunoreactivity at the single cell level. gp120 effects were diminished by inhibitors of protein kinase C (PKC) but not inhibitors of protein kinase A. PKC activity was upmodulated in gp120-transfected C6 cells and in the CNS of gp120 transgenic mice. Further, brain tissue from patients with HIV-1 encephalitis and from gp120 transgenic mice showed increased PKC immunoreactivity. Taken together, these results indicate that gp120-induced increases in PKC activity may contribute to the gliosis seen in gp120 transgenic mice as well as in HIV-1-infected humans and raise the question of whether dysregulation of signal transduction pathways represents a general mechanism of HIV-associated pathogenesis.

  View details for Web of Science ID A1996UB65600028

  View details for PubMedID 8609236

• SELECTIVE RESTIMULATION OF ANTIGEN OR ALLERGEN PREACTIVATED T-CELLS USING OKT3 F(AB)(2) RESULTS IN THE SECRETION OF TH-1 OR TH-2-LIKE CYTOKINE PATTERNS CLINICAL AND EXPERIMENTAL ALLERGY Jutel, M., WYSSCORAY, T., Carballido, J. M., Blaser, K., Muller, U. R., Pichler, W. J. 1995; 25 (11): 1108-1117

  Abstract

  The synthesis of IgE is regulated by cytokines secreted from T-helper cells. The studies on cytokine secretion by peripheral blood mononuclear cells (PBMC) upon stimulation with antigen or allergen are difficult due to low levels of cytokines, especially of interleukin-4 (IL-4).In this study we tried to establish a culture system, which could enable the measurement of the cytokine profiles in specifically activated cultures.Three methods to potentiate cytokine secretion were evaluated: PBMC from bee venom or house dust mite (Dermatophagoides pteronyssinus) allergic patients as well as normal subjects were stimulated either with the major bee venom allergen phospholipase A2 (PLA) or with the major D. pteronyssinus allergen (Der p 1) or with the control antigens tetanus toxoid (TT) and purified protein derivate (PPD). After 7 days of culture the cells were restimulated either with plastic bound OKT3 F(ab)2 monoclonal antibodies (MoAbs), with the appropriate antigen + antigen presenting cells or with IL-2. The secretion of cytokines (IL-4, IFN gamma) was measured after restimulation of the cultures (day 8).While OKT3 F(ab)2 was unable to activate resting T cells, it could restimulate preactivated cells. Restimulation with OKT3 F(ab)2 induced higher IL-4 and IFN gamma secretion than restimulation with IL-2 or antigen. TT and PLA stimulated a similar cytokine secretion profile in normal and PLA allergic subjects with substantial levels of both IL-4 and IFN gamma. In contrast, PPD induced virtually only IFN gamma secretion. Der p 1 stimulated mainly IL-4 secretion but also IFN gamma production in some mite allergic patients.We have established a cell culture system, which combines antigen specificity with a strong cytokine inducing signal provided by anti-CD3 MoAbs. TH-1 and TH-2 characteristic cytokine patterns can be observed in short-term PBMC cultures already after 8 days of culture.

  View details for Web of Science ID A1995TE20600013

  View details for PubMedID 8581844

• ANTIGEN-PRESENTING T-CELLS INDUCE THE DEVELOPMENT OF CYTOTOXIC CD4(+) T-CELLS .1. INVOLVEMENT OF THE CD80-CD28 ADHESION MOLECULES JOURNAL OF IMMUNOLOGY Mauri, D., WYSSCORAY, T., Gallati, H., Pichler, W. J. 1995; 155 (1): 118-127

  Abstract

  The development of cytotoxic CD4+ T lymphocytes that can kill target cells in a MHC class II-restricted manner was evaluated by comparing different APCs. B-lymphoblasts (B-LCL) pulsed with the superantigen staphylococcus enterotoxin B or allogeneic B-lymphoblasts induce CD4+ T cells without cytotoxic activity. In contrast, superantigen-pulsed, MHC class II+ T cell blasts or allogeneic T cell blasts preferentially induce the development of specific, MHC class II-restricted CD4+ cytotoxic effector cells. CD4+ T cell clones generated with T or B cell blasts as APCs (T- or B-APCs) differ in their cytolytic potential, but secrete a similar cytokine pattern. Our data implicate that activated T-APCs preferentially induce a cytotoxic, CD8+ and CD4+ T cell response. Because the density of CD80 expression is lower on activated T-APCs than on B-APCs, we studied the involvement of CD28 and CD80 adhesion molecules in the generation of CD4+ CTLs. Partial blockade of the CD80 molecule with a CTLA4-Ig fusion protein and with specific anti-CD80 mAbs on B-APCs enhanced the generation of CD4+ CTLs. Specific anti-CD86 mAbs, on the contrary, had no effect on the generation of CD4+ CTLs. In contrast, stimulation of CD28, the CD80 counter-receptor, with a cross-linked B7-Ig fusion protein or with an anti-CD28 mAb, inhibited the generation of CD4+ CTLs. Thus, a reduced interaction between CD80 and CD28 may be relevant for the induction of CD4+ CTLs. This shows a new and not yet described function of these adhesion molecules. This induction of a cytotoxic immune response by T cells as APCs may be relevant for the anticlonotypic regulation of T cells and for the depletion of CD4+ T cells in HIV infection.

  View details for Web of Science ID A1995RE57400015

  View details for PubMedID 7541409

• INCREASED CENTRAL-NERVOUS-SYSTEM PRODUCTION OF EXTRACELLULAR-MATRIX COMPONENTS AND DEVELOPMENT OF HYDROCEPHALUS IN TRANSGENIC MICE OVEREXPRESSING TRANSFORMING GROWTH-FACTOR-BETA-1 AMERICAN JOURNAL OF PATHOLOGY WYSSCORAY, T., Feng, L. L., Masliah, E., Ruppe, M. D., Lee, H. S., Toggas, S. M., Rockenstein, E. M., Mucke, L. 1995; 147 (1): 53-67

  Abstract

  A number of important neurological diseases, including HIV-1 encephalitis, Alzheimer's disease, and brain trauma, are associated with increased cerebral expression of the multifunctional cytokine transforming growth factor-beta 1 (TGF-beta 1). To determine whether overexpression of TGF-beta 1 within the central nervous system (CNS) can contribute to the development of neuropathological alterations, a bioactive form of TGF-beta 1 was expressed in astrocytes of transgenic mice. Transgenic mice with high levels of cerebral TGF-beta 1 expression developed a severe communicating hydrocephalus, seizures, motor incoordination, and early runting. While unmanipulated heterozygous transgenic mice from a low expressor line showed no such alterations, increasing TGF-beta 1 expression in this line by injury-induced astroglial activation or generation of homozygous offspring did result in the abnormal phenotype. Notably, astroglial overexpression of TGF-beta 1 consistently induced a strong upmodulation of the extracellular matrix proteins laminin and fibronectin in the CNS, particularly in the vicinity of TGF-beta 1-expressing perivascular astrocytes, but was not associated with obvious CNS infiltration by hematogenous cells. While low levels of extracellular matrix protein expression may assist in CNS wound repair and regeneration, excessive extracellular matrix deposition could result in the development of hydrocephalus. As an effective inducer of extracellular matrix components, TGF-beta 1 may also contribute to the development of other neuropathological alterations, eg, the formation of amyloid plaques in Alzheimer's disease.

  View details for Web of Science ID A1995RH02300007

  View details for PubMedID 7604885

• NONCYTOTOXIC HUMAN CD4(+) T-CELL CLONES PRESENTING AND SIMULTANEOUSLY RESPONDING TO AN ANTIGEN DIE OF APOPTOSIS CELLULAR IMMUNOLOGY Bettens, F., Frei, E., Frutig, K., Mauri, D., Pichler, W. J., WYSSCORAY, T. 1995; 161 (1): 72-78

  Abstract

  Activated T-cells expressing MHC class II surface antigens are able to present antigen and thus function as peptide-presenting cells (T-APCs). In this study we investigated whether antigen presentation by T-cells induced programmed cell death. As a model we used tetanus p30 peptide (aa 947-967)-specific, noncytotoxic CD4+ T-cell clones (C11 and C31). For experimental purposes these T-cell clones were stimulated (a) with p30 peptide-pulsed and fixed EBV-transformed antigen-presenting cells (B-APCs), (b) with p30-pulsed and fixed activated T-cells as APCs (as T-APCs we used either the T-cell clones themselves or an autologous T-cell clone (CT3) with p30 unrelated specificity), or (c) with soluble p30 peptide. The efficiency of antigen presentation was monitored by measuring proliferation as [3H]thymidine uptake. Apoptosis was measured by quantifying fragmented, cytoplasm DNA with the fluorescent dye 4,6-diamidino-2-phenylindole or by visualizing fragmented DNA by gel electrophoresis. Stimulation with p30-pulsed and fixed B-APCs or T-APCs induced proliferation but no apoptosis of the responding T-cells. However, stimulation of cloned T-cells with soluble peptide induced up-regulation of the FAS surface molecules and apoptosis, which was dependent on the peptide doses. Because cloned T-cells express HLA class II molecules, they can theoretically exert both functions at once: antigen presentation and antigen response when they are stimulated with soluble peptide. Because death by apoptosis is only seen under such circumstances, we suggest that T-cells simultaneously presenting and responding to an antigen die of apoptosis and thus contribute to the down-regulation of the immune response. Such phenomena might occur in HIV infection when activated CD4+ T-cells take up gp120 via their CD4 molecules, present it on their HLA class II surface antigens, and are simultaneously stimulated via their TCR.

  View details for Web of Science ID A1995QK25200010

  View details for PubMedID 7532549

• IMPROVED SENSITIZATION OF ANTIGEN-PRESENTING CELLS WITH TRANSFERRIN-BOUND PEPTIDES - ADVANTAGES IN COMPETITION FOR ANTIGEN PRESENTATION CELLULAR IMMUNOLOGY Mauri, D., WYSSCORAY, T., Brander, C., Pichler, W. J. 1994; 158 (1): 59-70

  Abstract

  T cells recognize peptides in association with major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). To sensitize APC for antigen presentation in vitro and in vivo, high concentrations of synthetic peptides can be added from the outside and bind to the MHC molecules, thereby mimicking naturally processed peptides. In this report we investigated whether the transferrin (Tf) molecule could be used as a carrier to introduce antigenic peptides into the antigen presentation pathway of APC. We coupled to Tf various MHC class II DR1 restricted peptides and compared the sensitization of DR1+ APC by the Tf-bound or by the soluble peptide, using peptide-specific T cell clones (TCC). The presentation of the Tf-bound peptides was MHC restricted and could be blocked by the fixation of the APC with glutaraldehyde or by the addition of an excess of Tf. Tf-bound peptides were more efficiently presented than soluble peptides, since smaller concentrations were required to sensitize APC. Moreover, they could compete with a soluble peptide for MHC restricted presentation with a very high efficiency if compared to soluble competing peptides. Tf peptide conjugates could even compete with the presentation of a native antigen like tetanus toxoid. Peptides bound to the transferrin molecule might be useful for immunization strategies, as the relevant bound peptides are efficiently presented to peptide-specific TCC.

  View details for Web of Science ID A1994PJ58700004

  View details for PubMedID 8087868

• COMPARATIVE-ANALYSIS OF SURFACE-ANTIGENS IN CULTURED HUMAN OUTER ROOT SHEATH-CELLS AND EPIDERMAL-KERATINOCYTES - PERSISTENCE OF LOW EXPRESSION OF CLASS-I MHC ANTIGENS IN OUTER ROOT SHEATH-CELLS IN-VITRO BRITISH JOURNAL OF DERMATOLOGY Limat, A., WYSSCORAY, T., Hunziker, T., Braathen, L. R. 1994; 131 (2): 184-190

  Abstract

  In the anagen human hair follicle, the epithelial cells from the infrainfundibular portion and the hair matrix cells express markedly lower numbers of major histocompatibility complex class I molecules than interfollicular epidermal keratinocytes. During the catagen phase of the hair cycle, class I expression on these cells increases, and activated macrophages aggregate around the follicle, which has led to the hypothesis that the cells to be resorbed are recognized by virtue of their low class I antigen expression. In the present study, we showed that, in vitro, outer root sheath cells also maintain a lower constitutive expression of MHC class I molecules compared with epidermal keratinocytes. In contrast, other surface antigens such as HLA-DR, -DP and -DQ, ICAM-1, LFA-3 and CD29, which are all known to participate in leucocyte-keratinocyte interactions, were similarly expressed in both cell types. Furthermore, interferon gamma strongly upregulated MHC class I and II and ICAM-1 expression in both cell types, whereas CD29 and LFA-3 remained unaffected. Tumour necrosis factor alpha, to a lesser extent, also upregulated MHC class I and ICAM-1 expression, but not class II expression. The differences in constitutive surface antigen expression of infrainfundibular outer root sheath cells compared with interfollicular epidermal keratinocytes emphasizes a distinct role of this cell type in the hair cycle, and possibly also in alopecia areata.

  View details for Web of Science ID A1994PB73500005

  View details for PubMedID 7917981

• T-CELLS AS ANTIGEN-PRESENTING CELLS IMMUNOLOGY TODAY Pichler, W. J., WYSSCORAY, T. 1994; 15 (7): 312-315

  Abstract

  Human T cells express major histocompatibility complex (MHC) class II antigens and adhesion molecules characteristic of antigen-presenting cells (APCs), and recent in vitro and in vivo evidence supports an antigen-presenting function for T cells. In this guise, T cells provide downregulatory signals for the immune response by inducing anergy in T cells that have already been activated and cytotoxicity in resting T cells. Here, Werner Pichler and Tony Wyss-Coray suggest that this may represent an important negative mechanism for T-cell homeostasis.

  View details for Web of Science ID A1994NV21300005

  View details for PubMedID 7522009

• A CELL-SURFACE ELISA FOR THE SCREENING OF MONOCLONAL-ANTIBODIES TO ANTIGENS ON VIABLE CELLS IN SUSPENSION JOURNAL OF IMMUNOLOGICAL METHODS Grunow, R., DAPUZZO, M., WYSSCORAY, T., Frutig, K., Pichler, W. J. 1994; 171 (1): 93-102

  Abstract

  To simplify the screening of monoclonal antibodies to different human T cell surface molecules a live cell enzyme-linked immunosorbent assay (cell ELISA) has been established and optimized. The assay was performed in 96-well plates. By using living human T lymphocytes in suspension surface modification by fixation or insolubilization of the cells was avoided. Several parameters influencing sensitivity and specificity were studied. About 150 ng/ml of mouse monoclonal antibodies to cell surface antigens could be detected when using 5 x 10(4) cells per well and a 1/1000 dilution of the anti-mouse IgG-alkaline phosphatase conjugate. This sensitivity permitted the primary screening of cell specific antibodies from hybridoma supernatants. The same detection limit was obtained in flow cytometric analysis. If required, the sensitivity of the cell ELISA could be increased using higher cell numbers and conjugate concentration. When analysing different cell lines with selected antibodies the cell ELISA was found to be as sensitive and specific as the fluorescence assay. The assay was applied to the screening of supernatants from hybridomas developed against human T helper cell clones and the detection of V beta specificities of T cell clones.

  View details for Web of Science ID A1994NK46000011

  View details for PubMedID 8176241

• Peptide-induced T cell clones: Specificity, MHC restriction, proliferation and cytokine pattern as a function of different stimulations 7th International Paul Ehrlich Seminar Pichler, W. J., Brander, C., Mauri, D., Frutig, K., WYSSCORAY, T. GUSTAV FISCHER VERLAG. 1994: 141–154

  Abstract

  CD4+ T cell clones were generated to tetanus toxin or to two tetanus toxin-derived peptides p2 (AA 830-834) and p30 (AA 947-976). 11 of the 24 p30-specific clones reacted to shorter p30 subunits (p301 or p302), and only 14 of the p2 or p30-specific clones reacted with TT presented by EBV-transformed B cell lines (B-LCL). The p30-specific clones were HLA-DP4 restricted. In contrast to autologous B cell lines, the majority of allogeneic, but HLA-DP4-positive cell lines failed to present p30 to the specific clones. We concluded that T cell clones are highly specific and that both, small alterations of the peptide length as well as discrete differences of the HLA-molecule may abrogate recognition of the peptide HLA complex by T cells. Moreover, use of peptides as stimulators of T cells may recruit and activate T cells which fail the "original" peptide, derived from normal antigen processing. Clones could usually be maintained in culture for 4-6 months, but with the help of freezing and thawing some clones are now available for over 2 years and still specific. Comparison of different autologous antigen-presenting cells, namely B-LCL and activated MHC class II-positive T cells revealed that not all clones were able to mount a proliferative response to peptide presentation by T cells, while all clones proliferated to B cells as APC. If stimulated with peptide and B-LCL, the clone proliferating to T cells as APC (so-called T responder clones) secreted a broad spectrum of cytokines (Th0-like) and were easier to maintain in culture. In contrast, clones which were unable to proliferate to peptide presentation, so-called T-nonresponder clones, showed a more restricted cytokine pattern and elevated or very low IL4/IFN gamma ratio upon antigen specific stimulation. However, all clones secreted at least small amounts of IL2, IL4, IFN gamma and TNF alpha, if stimulated by PMA and ionomycin. Thus, both chemical and antigen-specific stimulations should be considered if T cell clones are classified as Th1 or Th2, whereby those clones, which secrete a limited cytokine pattern after antigen stimulation only, might be named Th1 or Th2 like clones, while clones which even after PMA/ionomycin do not secrete all cytokines, might represent "real" Th1 or Th2 clones.

  View details for Web of Science ID A1994BD88X00012

  View details for PubMedID 7873053

• ANTIGEN-PRESENTING HUMAN T-CELLS AND ANTIGEN-PRESENTING B-CELLS INDUCE A SIMILAR CYTOKINE PROFILE IN SPECIFIC T-CELL CLONES EUROPEAN JOURNAL OF IMMUNOLOGY WYSSCORAY, T., Gallati, H., PRACHT, I., Limat, A., Mauri, D., Frutig, K., Pichler, W. J. 1993; 23 (12): 3350-3357

  Abstract

  One of the factors that may influence the cytokine secretion profile of a T cell is the antigen-presenting cell (APC). Since activated human T cells have been described to express major histocompatibility complex (MHC) class II molecules as well as costimulatory molecules for T cell activation, like e.g. ICAM-1, LFA-3 and B7, they might play a role as APC and be involved in the regulation of T-Tcell interactions. To define further the role of T cells as APC we tested their capacity to induce proliferation and cytokine production in peptide- or allospecific T cell clones and compared it with conventional APC, like B lymphoblasts (B-LCL) or HTLV-1-transformed T cells, or with non-classical APC, like activated keratinocytes or eosinophils. CD4+, DP-restricted T cell clones specific for a tetanus toxin peptide (amino acids 947-967) and CD4+, DR-restricted allospecific T cell clones produced interleukin (IL)-2, IL-4, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma) after phorbol 12-myristate 13-acetate and ionomycin stimulation and a more restricted cytokine pattern after antigen stimulation. Dose-response curves revealed that the antigen-presenting capacity of activated, MHC class II+, B7+ T cells was comparable to the one of B-LCL. Both APC induced the same cytokine profile in the T cell clones despite a weaker proliferative response with T cells as APC. Suboptimal stimulations resulted in a lower IFN-gamma/IL-4 ratio. Cytokine-treated, MHC class II+ keratinocytes and eosinophils differed in the expression of adhesion molecules and their capacity to restimulate T cell clones. The strongly ICAM-1-positive keratinocytes induced rather high cytokine levels. In contrast, eosinophils, which express only low densities of MHC class II and no or only low levels of adhesion molecules (B7, ICAM-1 and LFA3), provided a reduced signal resulting in a diminished IFN-gamma/IL-4 ratio. We conclude that non-classical APC differ in their capacity to restimulate T cell clones, whereby the intensity of MHC class II and adhesion molecules (B7, ICAM-1) expressed seems to determine the efficacy of this presentation.

  View details for Web of Science ID A1993MM68900042

  View details for PubMedID 7504995

• CARRIER-MEDIATED UPTAKE AND PRESENTATION OF A MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-RESTRICTED PEPTIDE EUROPEAN JOURNAL OF IMMUNOLOGY Brander, C., WYSSCORAY, T., Mauri, D., Bettens, F., Pichler, W. J. 1993; 23 (12): 3217-3223

  Abstract

  Antigenic peptides derived from endogenous or viral proteins can associate with class I or class II major histocompatibility complex (MHC) molecules, while exogenous antigens are endocytosed, processed intracellularly and presented on MHC class II molecules. Here we describe a method that allows the presentation of an MHC class I-restricted antigenic peptide on MHC class I molecules, although it was taken up from the outside. The HLA-A2-restricted influenza virus matrix protein-derived peptide (flu, 57-68) was used either in soluble form or coupled via an S-S bridge to transferrin (Tf-flu). Target cells were incubated with flu or Tf-flu and the effective antigen presentation was detected in a cytotoxicity assay using flu peptide-specific, HLA-A2-restricted CD8+ cytotoxic T lymphocytes. Sensitization of target cells with Tf-flu required 5 to 10 times higher molar concentrations of peptide compared to sensitization with soluble free peptide. The Tf-flu construct was taken up by the cells via the Tf receptor (CD71) as the binding of Tf-flu was blocked by an excess of Tf. In contrast to the flu peptide, cytotoxicity elicited by Tf-flu was blocked by brefeldin A but not by chloroquine nor inhibitors of intracellular reducing steps, like 1-buthionine-(s,r)-sulfoximine or n-ethylmaleimide. Presentation of the flu peptide derived from Tf-flu construct is not hindered in the mutant T2 cell line, which lacks genes coding for transporter proteins for antigenic peptides (TAP1/TAP2) and proteasomes subunits, suggesting that the processing pathway described in this report may involve TAP-independent steps.

  View details for Web of Science ID A1993MM68900025

  View details for PubMedID 8258336

• THE B7 ADHESION MOLECULE IS EXPRESSED ON ACTIVATED HUMAN T-CELLS - FUNCTIONAL INVOLVEMENT IN T-T CELL-INTERACTIONS EUROPEAN JOURNAL OF IMMUNOLOGY WYSSCORAY, T., MAURIHELLWEG, D., Baumann, K., Bettens, F., Grunow, R., Pichler, W. J. 1993; 23 (9): 2175-2180

  Abstract

  The B cell antigen B7 delivers a strong co-stimulatory signal for the activation of T cells by binding to its ligands CD28 and CTLA4. Here we demonstrate the surface expression of the B7 molecule on activated human T cells in vitro and under certain conditions in vivo and its functional importance in T-T cell interactions. B7 was detected by flow cytometry on antigen-specific CD4+ and allospecific CD8+ cloned T cells from different donors with anti-B7 monoclonal antibody (mAb) or a soluble CTLA4-C gamma 1 chimera molecule and by reverse transcription-polymerase chain reactions. The expression of B7 was up-regulated following restimulation of the T cell clones and peaked after 7-9 days. Moreover, we show that the B7 molecule on T cells is functionally involved in T-T cell interactions: mAb to CD28 and the CTLA4-Ig fusion protein could inhibit the proliferation of specific T cell clones in response to T cells as antigen-presenting cells (APC) or the proliferation of peripheral blood mononuclear cells in a primary allostimulation with activated T cells as stimulator cells. Finally, we found that B7 can be expressed on freshly isolated circulating T cells since in a preliminary study with a limited number of patients, B7 was present on a subset of CD3+ cells. B7 was expressed on activated T cells (CD4+ and CD8+) of certain human immunodeficiency virus (HIV)-infected individuals (0.5-20% B7+CD8+ cells) or some patients with autoimmune diseases whereas CD3+ cells of healthy individuals did not express B7. The coexpression of major histocompatibility complex class II molecules and B7 may be relevant for the capacity of activated T cells to function as APC. The expression of B7 on T cells in vivo in autoimmune diseases and in HIV infection may be important for a better understanding of these diseases.

  View details for Web of Science ID A1993LY55500018

  View details for PubMedID 7690323

• DISCRIMINATION OF HUMAN CD4-T CELL CLONES BASED ON THEIR REACTIVITY WITH ANTIGEN-PRESENTING T-CELLS EUROPEAN JOURNAL OF IMMUNOLOGY WYSSCORAY, T., Brander, C., Frutig, K., Pichler, W. J. 1992; 22 (9): 2295-2302

  Abstract

  In this report, we describe the discrimination of human T cell clones based on their reactivity with activated T cells as antigen-presenting cells (APC). CD4+ T cell clones specific for peptide P30 of tetanus toxin (amino acids 947-967) and restricted to the DP4 molecule were established and tested for proliferation to peptide presented either by peripheral blood mononuclear cells (PBMC), Epstein-Barr virus (EBV)-transformed B cells or major histocompatibility complex (MHC) class II-expressing T cells. We found two sets of T cell clones: one set proliferated to peptide presentation by PBMC, EBV-transformed B cell lines (EBV-B cells) and MHC class II+ T cells (termed T-responder clones), while the other set of clones was only stimulated to proliferate, if the peptide was presented by PBMC or EBV-B cells, but not by T cells (T-nonresponder clones). Nevertheless, these T-nonresponder clones recognized P30 also on T cells, as revealed by Ca2+ influx. The discrimination of the clones was not due to different avidities of the T cell receptors (TcR) of individual clones for the MHC-peptide complex as T-responder and T-nonresponder clones had similar dose-response curves to P30 presented by fixed EBV-B cell lines. Addition of cytokines [interleukin (IL)-1, IL-2, IL-4 and interferon gamma] did not change the proliferative response of the clones, which was consistent throughout an observation period of greater than 4 months. T-nonresponder clones, exposed to P30 on MHC class II-expressing T cells, became not anergic, as they could be restimulated by P30 presented on EBV-B cells. The measurement of a panel of T cell activation markers and adhesion molecules on T-responder and T-nonresponder clones revealed a higher expression of the CD28 molecule on the T-nonresponder clones. The data suggest that freshly cloned T cells can be differentiated by peptide presentation on classical (PBMC, EBV-B cells) or non-classical APC (class II+ T cells), and that this discrimination is further underlined by different levels of adhesion molecules.

  View details for Web of Science ID A1992JN49000017

  View details for PubMedID 1381313

• USE OF ANTIBODY PEPTIDE CONSTRUCTS TO DIRECT ANTIGENIC PEPTIDES TO T-CELLS - EVIDENCE FOR T-CELL PROCESSING AND PRESENTATION CELLULAR IMMUNOLOGY WYSSCORAY, T., Brander, C., Bettens, F., MIJIC, D., Pichler, W. J. 1992; 139 (1): 268-273

  Abstract

  Human T cells can express MHC-class II products and were shown to be potential antigen-presenting cells. However, they are unable to capture the antigen and only antigens, which bind to T cell membranes such as the gp120 glycoprotein of HIV, are internalized, processed, and presented by T cells. To better understand the role of T cells as antigen-presenting cells, we established a method which overcomes the lack of antigen capture by T cells. Antigen (tetanus toxoid, TT) or an antigenic peptide of TT (residue 830-843, P2) was coupled to antibodies directed to T cell surface molecules such as CD2, CD4, CD8. Antibody/TT and antibody/P2 constructs stimulated P2-specific T cell clones in the absence of accessory cells, if the antibody recognized a T cell surface structure. Compared to the peptide alone, a 100-500 times lower molar concentration of the antibody/peptide construct was required to achieve a similar proliferative response. T cell stimulation via the constructs involved intracellular processing, as nonspecific, glutaraldehyde fixed T cell lines pulsed with the constructs could present the peptide and processing inhibitors like Leupeptin or Chloroquine inhibited the development of a proliferative response to the constructs. Our data underline the ability of T cells to function as antigen-processing and -presenting cells and show that antibody/antigen or antibody/peptide constructs are able to direct a certain antigen or peptide to a T cell. Antibody/peptide constructs may be interesting tools to better understand antigen processing and to study the consequences of antigen presentation by different cells.

  View details for Web of Science ID A1992GW21300025

  View details for PubMedID 1728968