Katrin Andreasson

All Publications

• Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies. Science (New York, N.Y.) Minhas, P. S., Jones, J. R., Latif-Hernandez, A., Sugiura, Y., Durairaj, A. S., Wang, Q., Mhatre, S. D., Uenaka, T., Crapser, J., Conley, T., Ennerfelt, H., Jung, Y. J., Liu, L., Prasad, P., Jenkins, B. C., Ay, Y. A., Matrongolo, M., Goodman, R., Newmeyer, T., Heard, K., Kang, A., Wilson, E. N., Yang, T., Ullian, E. M., Serrano, G. E., Beach, T. G., Wernig, M., Rabinowitz, J. D., Suematsu, M., Longo, F. M., McReynolds, M. R., Gage, F. H., Andreasson, K. I. 2024; 385 (6711): eabm6131

  Abstract

  Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid beta and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.

  View details for DOI 10.1126/science.abm6131

  View details for PubMedID 39172838

• TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models. Nature neuroscience Wilson, E. N., Wang, C., Swarovski, M. S., Zera, K. A., Ennerfelt, H. E., Wang, Q., Chaney, A., Gauba, E., Ramos Benitez, J. A., Le Guen, Y., Minhas, P. S., Panchal, M., Tan, Y. J., Blacher, E., A Iweka, C., Cropper, H., Jain, P., Liu, Q., Mehta, S. S., Zuckerman, A. J., Xin, M., Umans, J., Huang, J., Durairaj, A. S., Serrano, G. E., Beach, T. G., Greicius, M. D., James, M. L., Buckwalter, M. S., McReynolds, M. R., Rabinowitz, J. D., Andreasson, K. I. 2024

  Abstract

  Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

  View details for DOI 10.1038/s41593-024-01610-w

  View details for PubMedID 38539014

  View details for PubMedCentralID 4369837

• Aging disrupts circadian gene regulation and function in macrophages. Nature immunology Blacher, E., Tsai, C., Litichevskiy, L., Shipony, Z., Iweka, C. A., Schneider, K. M., Chuluun, B., Heller, H. C., Menon, V., Thaiss, C. A., Andreasson, K. I. 1800

  Abstract

  Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.

  View details for DOI 10.1038/s41590-021-01083-0

  View details for PubMedID 34949832

• Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature Minhas, P. S., Latif-Hernandez, A., McReynolds, M. R., Durairaj, A. S., Wang, Q., Rubin, A., Joshi, A. U., He, J. Q., Gauba, E., Liu, L., Wang, C., Linde, M., Sugiura, Y., Moon, P. K., Majeti, R., Suematsu, M., Mochly-Rosen, D., Weissman, I. L., Longo, F. M., Rabinowitz, J. D., Andreasson, K. I. 2021

  Abstract

  Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.

  View details for DOI 10.1038/s41586-020-03160-0

  View details for PubMedID 33473210

• Soluble TREM2 is elevated in Parkinson's disease subgroups with increased CSF tau. Brain : a journal of neurology Wilson, E. N., Swarovski, M. S., Linortner, P. n., Shahid, M. n., Zuckerman, A. J., Wang, Q. n., Channappa, D. n., Minhas, P. S., Mhatre, S. D., Plowey, E. D., Quinn, J. F., Zabetian, C. P., Tian, L. n., Longo, F. M., Cholerton, B. n., Montine, T. J., Poston, K. L., Andreasson, K. I. 2020

  Abstract

  Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-β and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-β and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-β and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-β biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.

  View details for DOI 10.1093/brain/awaa021

  View details for PubMedID 32065223

• Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity Nature Immunology Liu, Q., Johnson, E., et al 2019

  View details for DOI 10.1038/s41590-019-0421-2

• Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nature immunology Minhas, P. S., Liu, L., Moon, P. K., Joshi, A. U., Dove, C., Mhatre, S., Contrepois, K., Wang, Q., Lee, B. A., Coronado, M., Bernstein, D., Snyder, M. P., Migaud, M., Majeti, R., Mochly-Rosen, D., Rabinowitz, J. D., Andreasson, K. I. 2018

  Abstract

  Recent advances highlight a pivotal role for cellular metabolism in programming immune responses. Here, we demonstrate that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation. Isotope tracer studies revealed that macrophage NAD+ derives substantially from KP metabolism of tryptophan. Genetic or pharmacological blockade of de novo NAD+ synthesis depleted NAD+, suppressed mitochondrial NAD+-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD+ synthesis by limiting the conversion of downstream quinolinate to NAD+, a profile recapitulated in aging macrophages. Increasing de novo NAD+ generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses. Thus, KP-derived NAD+ operates as a metabolic switch to specify macrophage effector responses. Breakdown of de novo NAD+ synthesis may underlie declining NAD+ levels and rising innate immune dysfunction in aging and age-associated diseases.

  View details for PubMedID 30478397

• Targeting innate immunity for neurodegenerative disorders of the central nervous system. Journal of neurochemistry Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., Monsonego, A., O'Banion, M. K., Pekny, M., Puschmann, T., Russek-Blum, N., Sandusky, L. A., Selenica, M. B., Takata, K., Teeling, J., Town, T., Van Eldik, L. J. 2016; 138 (5): 653-693

  Abstract

  Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article.

  View details for DOI 10.1111/jnc.13667

  View details for PubMedID 27248001

• Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice BRAIN Woodling, N. S., Colas, D., Wang, Q., Minhas, P., Panchal, M., Liang, X., Mhatre, S. D., Brown, H., Ko, N., Zagol-Ikapitte, I., Van der Hart, M., Khroyan, T. V., Chuluun, B., Priyam, P. G., Milne, G. L., Rassoulpour, A., Boutaud, O., Manning-Bog, A. B., Heller, H. C., Andreasson, K. I. 2016; 139: 2063-2081

  Abstract

  Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.

  View details for DOI 10.1093/brain/aww117

  View details for Web of Science ID 000379763000026

  View details for PubMedID 27190010

  View details for PubMedCentralID PMC4939702

• Microglial Malfunction: The Third Rail in the Development of Alzheimer's Disease. Trends in neurosciences Mhatre, S. D., Tsai, C. A., Rubin, A. J., James, M. L., Andreasson, K. I. 2015; 38 (10): 621-636

  Abstract

  Studies of Alzheimer's disease (AD) have predominantly focused on two major pathologies: amyloid-β (Aβ) and hyperphosphorylated tau. These misfolded proteins can accumulate asymptomatically in distinct regions over decades. However, significant Aβ accumulation can be seen in individuals who do not develop dementia, and tau pathology limited to the transentorhinal cortex, which can appear early in adulthood, is usually clinically silent. Thus, an interaction between these pathologies appears to be necessary to initiate and propel disease forward to widespread circuits. Recent multidisciplinary findings strongly suggest that the third factor required for disease progression is an aberrant microglial immune response. This response may initially be beneficial; however, a maladaptive microglial response eventually develops, fueling a feed-forward spread of tau and Aβ pathology.

  View details for DOI 10.1016/j.tins.2015.08.006

  View details for PubMedID 26442696

  View details for PubMedCentralID PMC4670239

• Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models JOURNAL OF CLINICAL INVESTIGATION Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Hang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., Andreasson, K. I. 2015; 125 (1): 350-364

  Abstract

  Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

  View details for DOI 10.1172/JCI77487

  View details for Web of Science ID 000347747300037

  View details for PubMedID 25485684

• Plasma Aβ42/Aβ40 is sensitive to early cerebral amyloid accumulation and predicts risk of cognitive decline across the Alzheimer's disease spectrum. Alzheimer's & dementia : the journal of the Alzheimer's Association Trelle, A. N., Young, C. B., Vossler, H., Ramos Benitez, J., Cody, K. A., Mendiola, J. H., Swarovski, M. S., Guen, Y. L., Feinstein, I., Butler, R. R., Channappa, D., Romero, A., Park, J., Shahid-Besanti, M., Corso, N. K., Chau, K., Smith, A. N., Skylar-Scott, I., Yutsis, M. V., Fredericks, C. A., Tian, L., Younes, K., Kerchner, G. A., Deutsch, G. K., Davidzon, G. A., Sha, S. J., Henderson, V. W., Longo, F. M., Greicius, M. D., Wyss-Coray, T., Andreasson, K. I., Poston, K. L., Wagner, A. D., Mormino, E. C., Wilson, E. N. 2024

  Abstract

  The availability of amyloid beta (Aβ) targeting therapies for Alzheimer's disease (AD) is increasing the demand for scalable biomarkers that are sensitive to early cerebral Aβ accumulation.We evaluated fully-automated Lumipulse plasma Aβ42/Aβ40 immunoassays for detecting cerebral Aβ in 457 clinically unimpaired (CU) and clinically impaired (CI) Stanford Alzheimer's Disease Research Center (Stanford ADRC) participants and 186 CU in the Stanford Aging and Memory Study (SAMS). Longitudinal change in ADRC plasma Aβ42/Aβ40 and cognition and cross-sectional associations with SAMS memory and tau positron emission tomography (PET) were examined.Plasma Aβ42/Aβ40 exhibited high performance in detecting amyloid positivity defined by PET (area under the curve [AUC]: 0.885, 95% confidence interval [CI]: 0.816-0.955). Once abnomal, plasma Aβ42/Aβ40 remained low and predicted cognitive decline in both CU and CI individuals. Among SAMS CU, plasma Aβ42/Aβ40 was associated with poorer hippocampal-dependent memory and elevated tau accumulation.Lumipulse plasma Aβ42/Aβ40 is a scalable assay for detection of cerebral Aβ and prediction of risk for cognitive decline across the AD continuum.Lumipulse plasma amyloid beta (Aβ)42/Aβ40 exhibited high accuracy in detecting amyloid positivity. Plasma amyloid-positive (Aβ+) individuals exhibited stability of Aβ42/Aβ40 over time. Plasma Aβ42/Aβ40 predicted future cognitive decline across the Alzheimer's disease (AD) spectrum. Plasma Aβ42/Aβ40 was sensitive to memory and tau burden in clinically unimpaired older adults.

  View details for DOI 10.1002/alz.14442

  View details for PubMedID 39713875

• Neuroinflammation in Alzheimer disease. Nature reviews. Immunology Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., Edison, P., Ramirez, A., Cruchaga, C., Lambert, J. C., Laza, A. R., Sanchez-Mut, J. V., Fischer, A., Castro-Gomez, S., Stein, T. D., Kleineidam, L., Wagner, M., Neher, J. J., Cunningham, C., Singhrao, S. K., Prinz, M., Glass, C. K., Schlachetzki, J. C., Butovsky, O., Kleemann, K., De Jaeger, P. L., Scheiblich, H., Brown, G. C., Landreth, G., Moutinho, M., Grutzendler, J., Gomez-Nicola, D., McManus, R. M., Andreasson, K., Ising, C., Karabag, D., Baker, D. J., Liddelow, S. A., Verkhratsky, A., Tansey, M., Monsonego, A., Aigner, L., Dorothée, G., Nave, K. A., Simons, M., Constantin, G., Rosenzweig, N., Pascual, A., Petzold, G. C., Kipnis, J., Venegas, C., Colonna, M., Walter, J., Tenner, A. J., O'Banion, M. K., Steinert, J. R., Feinstein, D. L., Sastre, M., Bhaskar, K., Hong, S., Schafer, D. P., Golde, T., Ransohoff, R. M., Morgan, D., Breitner, J., Mancuso, R., Riechers, S. P. 2024

  Abstract

  Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.

  View details for DOI 10.1038/s41577-024-01104-7

  View details for PubMedID 39653749

  View details for PubMedCentralID 9009508

• 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

• Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease. Annals of neurology Abdelnour, C., Young, C. B., Shahid-Besanti, M., Smith, A., Wilson, E. N., Ramos Benitez, J., Vossler, H., Plastini, M. J., Winer, J. R., Kerchner, G. A., Cholerton, B., Andreasson, K. I., Henderson, V. W., Yutsis, M., Montine, T. J., Tian, L., Mormino, E. C., Poston, K. L. 2024

  Abstract

  To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD).We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aβ42, and CSF Aβ42/Aβ40 or amyloid-β PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes.Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment.Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024.

  View details for DOI 10.1002/ana.27003

  View details for PubMedID 38888142

• 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

• Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra. Annals of clinical and translational neurology Plastini, M. J., Abdelnour, C., Young, C. B., Wilson, E. N., Shahid-Besanti, M., Lamoureux, J., Andreasson, K. I., Kerchner, G. A., Montine, T. J., Henderson, V. W., Poston, K. L. 2024

  Abstract

  More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD.Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra.Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003).Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

  View details for DOI 10.1002/acn3.52034

  View details for PubMedID 38436140

• 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

• Immunosuppression with Targeted Therapies Reduces Morbidity and Mortality in Pre-Capillary Pulmonary Hypertension Associated with Systemic Sclerosis: A EUSTAR Analysis Bruni, C., Fretheim, H., Tofani, L., Weber, Y., Hachulla, E., Carreira, P., Giuggioli, D., Airo, P., Siegert, E., Mueller-Ladner, U., Cerinic, M., Riemekasten, G., Simeon-Aznar, C., de Vries-Bouwstra, J., Saketkoo, L., Distler, J., Balbir-Gurman, A., Castellvi, I., Zanatta, E., Smith, V., Denton, C., Maurer, B., Giollo, A., Iannone, F., Dagna, L., Truchetet, M., Kuwana, M., Allanore, Y., Tanaka, Y., Martin, M., Rosato, E., Gheorghiu, A., Del Galdo, F., Solanki, K., Vacca, A., Resende, C., Vieira, S., Czirjak, L., Barisic, M., Cantatore, F., Riccieri, V., Andreasson, K., Chung, L., Muller, C., Opris-Belinski, D., Rednic, S., Sfikakis, P., Levy, Y., Hoffmann-Vold, A., Distler, O., Hsu, V., Heitmann, S., Moroncini, G., Iudici, M., Henes, J., De langhe, E., Herrick, A., Montecucco, C. WILEY. 2023: 3385-3389

  View details for Web of Science ID 001190014303197

• PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis. Science translational medicine Chaney, A. M., Cropper, H. C., Jain, P., Wilson, E., Simonetta, F., Johnson, E. M., Alam, I. S., Patterson, I. T., Swarovski, M., Stevens, M. Y., Wang, Q., Azevedo, C., Nagy, S. C., Ramos Benitez, J., Deal, E. M., Vogel, H., Andreasson, K. I., James, M. L. 2023; 15 (702): eabm6267

  Abstract

  Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.

  View details for DOI 10.1126/scitranslmed.abm6267

  View details for PubMedID 37379371

• Myeloid deficiency of the intrinsic clock protein BMAL1 accelerates cognitive aging by disrupting microglial synaptic pruning. Journal of neuroinflammation Iweka, C. A., Seigneur, E., Hernandez, A. L., Paredes, S. H., Cabrera, M., Blacher, E., Pasternak, C. T., Longo, F. M., de Lecea, L., Andreasson, K. I. 2023; 20 (1): 48

  Abstract

  Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11bcre;Bmallox/lox mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1-deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11bcre;Bmallox/lox mice also showed deficits in the sleep-wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain.

  View details for DOI 10.1186/s12974-023-02727-8

  View details for PubMedID 36829230

  View details for PubMedCentralID 8157517

• Reduced expression of the cell intrinsic clock protein Bmal1 in myeloid cells accelerates cognitive decline and alters microglial function in aging mice Iweka, C., Seigneur, E., Latif-Hernandez, A., Paredes, S., Cabrera, M., Blacher, E., Wang, Q., Longo, F., DeLecea, L., Andreasson, K. AMER SOC CELL BIOLOGY. 2023: 761

  View details for Web of Science ID 001051001303275

• 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

• 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

• Odorant receptors in macrophages: potential targets for atherosclerosis. Trends in immunology Wang, C., Andreasson, K. I. 2022

  Abstract

  In a recent report, Orecchioni et al. identify a role for the olfactory receptor (OR) Olfr2 and its human ortholog OR6A2 in atherosclerosis. Vascular macrophage Olfr2 binds octanal, a product of lipid peroxidation, activating the NLRP3 inflammasome and IL-1beta secretion, and driving atherosclerosis pathology. Thus, OR6A2 inhibitors may represent a promising therapy for atherosclerosis.

  View details for DOI 10.1016/j.it.2022.02.006

  View details for PubMedID 35283015

• Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nature immunology Zhou, L., Zhou, W., Joseph, A. M., Chu, C., Putzel, G. G., Fang, B., Teng, F., Lyu, M., Yano, H., Andreasson, K. I., Mekada, E., Eberl, G., Sonnenberg, G. F. 1800; 23 (2): 251-261

  Abstract

  Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.

  View details for DOI 10.1038/s41590-021-01110-0

  View details for PubMedID 35102343

• 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

• Plasma Biomarkers of Tau and Neurodegeneration During Major Cardiac and Noncardiac Surgery. JAMA neurology Feinstein, I., Wilson, E. N., Swarovski, M. S., Andreasson, K. I., Angst, M. S., Greicius, M. D. 2021

  View details for DOI 10.1001/jamaneurol.2021.2823

  View details for PubMedID 34542578

• A mitochondrial membrane-bridging machinery mediates signal transduction of intramitochondrial oxidation. Nature metabolism Li, L., Conradson, D. M., Bharat, V., Kim, M. J., Hsieh, C., Minhas, P. S., Papakyrikos, A. M., Durairaj, A. S., Ludlam, A., Andreasson, K. I., Partridge, L., Cianfrocco, M. A., Wang, X. 2021

  Abstract

  Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60-Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson's disease and Friedreich's ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress.

  View details for DOI 10.1038/s42255-021-00443-2

  View details for PubMedID 34504353

• Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease. Neurology Trelle, A. N., Carr, V. A., Wilson, E. N., Swarovski, M. S., Hunt, M. P., Toueg, T. N., Tran, T. T., Channappa, D. n., Corso, N. K., Thieu, M. K., Jayakumar, M. n., Nadiadwala, A. n., Guo, W. n., Tanner, N. J., Bernstein, J. D., Litovsky, C. P., Guerin, S. A., Khazenzon, A. M., Harrison, M. B., Rutt, B. K., Deutsch, G. K., Chin, F. T., Davidzon, G. A., Hall, J. N., Sha, S. J., Fredericks, C. A., Andreasson, K. I., Kerchner, G. A., Wagner, A. D., Mormino, E. C. 2021

  Abstract

  To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer's disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied 'target' objects, novel 'foil' objects, and perceptually similar 'lure' objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

  View details for DOI 10.1212/WNL.0000000000011477

  View details for PubMedID 33408146

• TAM-ping down amyloid in Alzheimer's disease. Nature immunology Wilson, E. N., Andreasson, K. I. 2021

  View details for DOI 10.1038/s41590-021-00918-0

  View details for PubMedID 33859407

• The Dueling Duo: IL10 and TNF Face Off in Microglial Recovery from Endotoxin Challenge. Immunity Minhas, P. S., Durairaj, A. S., Andreasson, K. I. 2020; 53 (5): 897–99

  Abstract

  The molecular mechanisms that restore microglial quiescence after acute stimulation remain largely unexplored, unlike those that drive microglial activation. In this issue of Immunity, Shemer etal. discover that the microglial IL-10 receptor counteracts the pro-inflammatory effects of TNF to allow restoration of microglial quiescence after peripheral endotoxin challenge.

  View details for DOI 10.1016/j.immuni.2020.10.016

  View details for PubMedID 33207212

• TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis Chaney, A., Wilson, E., Jain, P., Cropper, H., Swarovski, M., Lucot, K., Vogel, H., Andreasson, K., James, M. L. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500179

• Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy. Journal of neuroinflammation Haileselassie, B. n., Joshi, A. U., Minhas, P. S., Mukherjee, R. n., Andreasson, K. I., Mochly-Rosen, D. n. 2020; 17 (1): 36

  Abstract

  Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis.We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction.LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment.LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy.

  View details for DOI 10.1186/s12974-019-1689-8

  View details for PubMedID 31987040

• Loss of DP1 Aggravates Vascular Remodeling in Pulmonary Arterial Hypertension via mTORC1 Signaling. American journal of respiratory and critical care medicine He, Y. n., Zuo, C. n., Jia, D. n., Bai, P. n., Kong, D. n., Chen, D. n., Liu, G. n., Li, J. n., Wang, Y. n., Chen, G. n., Yan, S. n., Xiao, B. n., Zhang, J. n., Piao, L. n., Li, Y. n., Deng, Y. n., Li, B. n., Roux, P. P., Andreasson, K. I., Breyer, R. M., Su, Y. n., Wang, J. n., Lyu, A. n., Shen, Y. n., Yu, Y. n. 2020

  Abstract

  Vascular remodeling, including smooth muscle cell hypertrophy and proliferation, is the key pathological feature of pulmonary arterial hypertension (PAH). Prostaglandin (PG) I2 analogs (baraprost, iloprost, and treprostinil) are effective in the treatment of PAH. Of note, the clinically favorable effects of treprostinil in severe PAH may be attributable to concomitant activation of PGD2 receptor subtype 1 (DP1).To study the role of DP1 in the progression of PAH and its underlying mechanism.DP1 expression was downregulated in hypoxia-treated PASMCs and in pulmonary arteries (PAs) from rodent PAH models and idiopathic PAH patients. DP1 deletion exacerbated PA remodeling in hypoxia-induced PAH, whereas pharmacological activation or forced expression of DP1 receptor had the opposite effect in different rodent models. DP1 deficiency promoted PASMC hypertrophy and proliferation in response to hypoxia via induction of mammalian target of rapamycin complex (mTORC) 1 activity. Rapamycin, an inhibitor of mTORC1, alleviated the hypoxia-induced exacerbation of PAH in DP1-/- mice. DP1 activation facilitated raptor dissociation from mTORC1 complex and suppressed mTORC1 activity through protein kinase A (PKA)-dependent phosphorylation of raptor at Ser791. Moreover, treprostinil treatment blocked the progression of hypoxia-induced PAH in mice in part by targeting DP1 receptor.DP1 activation attenuates hypoxia-induced PA remodeling and PAH through PKA-mediated dissociation of raptor from the mTORC1 complex. These results suggest that DP1 receptor may serve as a therapeutic target for the management of PAH.

  View details for DOI 10.1164/rccm.201911-2137OC

  View details for PubMedID 31917615

• Author Correction: Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nature neuroscience Joshi, A. U., Minhas, P. S., Liddelow, S. A., Haileselassie, B. n., Andreasson, K. I., Dorn, G. W., Mochly-Rosen, D. n. 2020

  View details for DOI 10.1038/s41593-020-00774-5

  View details for PubMedID 33324000

• PGE(2) signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liu, Q., Liang, X., Wang, Q., Wilson, E. N., Lam, R., Wang, J., Kong, W., Tsai, C., Pan, T., Larkin, P. B., Shamloo, M., Andreasson, K. I. 2019; 116 (20): 10019–24

  View details for DOI 10.1073/pnas.1818544116

  View details for Web of Science ID 000467804000053

• PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America Liu, Q. n., Liang, X. n., Wang, Q. n., Wilson, E. N., Lam, R. n., Wang, J. n., Kong, W. n., Tsai, C. n., Pan, T. n., Larkin, P. B., Shamloo, M. n., Andreasson, K. I. 2019

  Abstract

  The inflammatory prostaglandin E2 (PGE2) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2lox/lox mice attenuated brain infiltration of Cd11b+CD45hi macrophages and CD45+Ly6Ghi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreERT2 (ROSACreER);EP2lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2lox/lox mice, unlike EP2-/- mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.

  View details for PubMedID 31036664

• Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer's disease related pathology. Acta neuropathologica communications Joshi, A. U., Van Wassenhove, L. D., Logas, K. R., Minhas, P. S., Andreasson, K. I., Weinberg, K. I., Chen, C. H., Mochly-Rosen, D. n. 2019; 7 (1): 190

  Abstract

  Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer's Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

  View details for DOI 10.1186/s40478-019-0839-7

  View details for PubMedID 31829281

• Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nature neuroscience Joshi, A. U., Minhas, P. S., Liddelow, S. A., Haileselassie, B. n., Andreasson, K. I., Dorn, G. W., Mochly-Rosen, D. n. 2019; 22 (10): 1635–48

  Abstract

  In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

  View details for DOI 10.1038/s41593-019-0486-0

  View details for PubMedID 31551592

• Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation NATURE IMMUNOLOGY Minhas, P. S., Liu, L., Moon, P. K., Joshi, A. U., Dove, C., Mhatre, S., Contrepois, K., Wang, Q., Lee, B. A., Coronado, M., Bernstein, D., Snyder, M. P., Migaud, M., Majeti, R., Mochly-Rosen, D., Rabinowitz, J. D., Andreasson, K. I. 2019; 20 (1): 50-+

  View details for DOI 10.1038/s41590-018-0255-3

  View details for Web of Science ID 000456273900014

• Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science translational medicine Lin, G. L., Wilson, K. M., Ceribelli, M. n., Stanton, B. Z., Woo, P. J., Kreimer, S. n., Qin, E. Y., Zhang, X. n., Lennon, J. n., Nagaraja, S. n., Morris, P. J., Quezada, M. n., Gillespie, S. M., Duveau, D. Y., Michalowski, A. M., Shinn, P. n., Guha, R. n., Ferrer, M. n., Klumpp-Thomas, C. n., Michael, S. n., McKnight, C. n., Minhas, P. n., Itkin, Z. n., Raabe, E. H., Chen, L. n., Ghanem, R. n., Geraghty, A. C., Ni, L. n., Andreasson, K. I., Vitanza, N. A., Warren, K. E., Thomas, C. J., Monje, M. n. 2019; 11 (519)

  Abstract

  Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

  View details for DOI 10.1126/scitranslmed.aaw0064

  View details for PubMedID 31748226

• TREM1-TARGETED PET IMAGING OF TUMOR-ASSOCIATED MACROPHAGES IN AN ORTHOTOPIC GLIOBLASTOMA MOUSE MODEL Johnson, E., Murty, S., Mayer, A., Tsai, C., Mehta, S., Ilovich, O., Massoud, T., Andreasson, K., James, M. OXFORD UNIV PRESS INC. 2017: 249

  View details for Web of Science ID 000415152503382

• Anti-Inflammatory and Neuroprotective Effects of PGE(2) EP4 Signaling in Models of Parkinson's Disease JOURNAL OF NEUROIMMUNE PHARMACOLOGY Pradhan, S. S., Salinas, K., Garduno, A. C., Johansson, J. U., Wang, Q., Manning-Bog, A., Andreasson, K. I. 2017; 12 (2): 292-304

  Abstract

  Inflammation is a ubiquitous factor accompanying normal aging and neurodegeneration, and recent studies indicate a major contribution of inducible cyclooxygenase (COX-2) and its downstream prostaglandin signaling pathways in modulating neuroinflammatory responses and neuronal function. We have previously shown that the prostaglandin PGE2 receptor EP4 suppresses innate immune responses in models of systemic inflammation. Here we investigated the role of the EP4 receptor in models of Parkinson's disease (PD). Systemic co-administration of the EP4 agonist ONO-AE1-329 with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prevented loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) without significant changes in glial activation, suggesting a potent neuroprotective effect of EP4 signaling in this acute model of DA neuronal loss. Cell-specific conditional ablation of EP4 in Cd11bCre;EP4(lox/lox) mice exacerbated MPTP-associated glial activation and T-cell infiltration in SNpc, consistent with anti-inflammatory functions of microglial EP4 signaling. In vitro, in primary microglia stimulated with oligomeric α-synuclein, EP4 receptor activation suppressed generation of pro-inflammatory and oxidative stress factors. Taken together, these findings suggest a dual neuroprotective and anti-inflammatory mechanism of action by the EP4 receptor in models of PD.

  View details for DOI 10.1007/s11481-016-9713-6

  View details for Web of Science ID 000400077600008

• Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids. FASEB journal Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. 2017

  Abstract

  Unlike other agonists that cause transient endothelial cell (EC) response, the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine oxidation (OxPAPC) that contain cyclopenthenone groups, which recapitulate prostaglandin-like structure, cause sustained enhancement of the pulmonary EC barrier. The mechanisms that drive the sustained effects by OxPAPC remain unexplored. On the basis of the structural similarity of isoprostanoid moieties that are present in full-length oxygenated PAPC species, we used an inhibitory approach to perform the screening of prostanoid receptors as potential candidates that mediate OxPAPC effects. Results show that only prostaglandin E receptor-4 (EP4) was involved and mediated the sustained phase of the barrier-enhancing effects of OxPAPC that are associated with the activation of Rac GTPase and its cytoskeletal targets. EC incubation with OxPAPC also induced EP4 mRNA expression in pulmonary ECs and lung tissue. EP4 knockdown using gene-specific small interfering RNA did not affect the rapid phase of OxPAPC-induced EC barrier enhancement or the protective effects against thrombin-induced EC permeability, but abolished the advanced barrier enhancement phase and suppressed the protective effects of OxPAPC against more sustained EC barrier dysfunction and cell inflammatory response caused by TNF-α. Endothelial-specific knockout of the EP4 receptor in mice attenuated the protective effect of intravenous OxPAPC administration in the model of acute lung injury caused by intratracheal injection of LPS. Taken together, these results demonstrate a novel role for prostaglandin receptor EP4 in the mediation of barrier-enhancing and anti-inflammatory effects caused by oxidized phospholipids.-Oskolkova, O., Gawlak, G., Tian, Y., Ke, Y., Sarich, N., Son, S., Andreasson, K., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Prostaglandin E receptor-4 receptor mediates endothelial barrier-enhancing and anti-inflammatory effects of oxidized phospholipids.

  View details for DOI 10.1096/fj.201601232RR

  View details for PubMedID 28572443

• Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor. Molecular biology of the cell Ohmura, T., Tian, Y., Sarich, N., Ke, Y., Meliton, A., Shah, A. S., Andreasson, K., Birukov, K. G., Birukova, A. A. 2017

  Abstract

  The role of prostaglandin A2 (PGA2) in modulation of vascular endothelial function is unknown. We investigated effects of PGA2 on pulmonary endothelial cell (EC) permeability and inflammatory activation and identified a receptor mediating these effects. PGA2 enhanced the EC barrier and protected against barrier dysfunction caused by vasoactive peptide thrombin and proinflammatory bacterial wall lipopolysaccharide (LPS). Receptor screening using pharmacological and molecular inhibitory approaches identified EP4 as a novel PGA2 receptor. EP4 mediated barrier-protective effects of PGA2 by activating Rap1/Rac1 GTPase and protein kinase A targets at cell adhesions and cytoskeleton: VE-cadherin, p120-catenin, ZO-1, cortactin, and VASP. PGA2 also suppressed LPS-induced inflammatory signaling by inhibiting the NFκB pathway and expression of EC adhesion molecules ICAM1 and VCAM1. These effects were abolished by pharmacological or molecular inhibition of EP4. In vivo, PGA2 was protective in two distinct models of acute lung injury (ALI): LPS-induced inflammatory injury and two-hit ALI caused by suboptimal mechanical ventilation and injection of thrombin receptor-activating peptide. These protective effects were abolished in mice with endothelial-specific EP4 knockout. The results suggest a novel role for the PGA2-EP4 axis in vascular EC protection that is critical for improvement of pathological states associated with increased vascular leakage and inflammation.

  View details for DOI 10.1091/mbc.E16-09-0639

  View details for PubMedID 28428256

• Gpr124 is essential for blood-brain barrier integrity in central nervous system disease NATURE MEDICINE Chang, J., Mancuso, M. R., Maier, C., Liang, X., Yuki, K., Yang, L., Kwong, J. W., Wang, J., Rao, V., Vallon, M., Kosinski, C., Zhang, J. J., Mah, A. T., Xu, L., Li, L., Gholamin, S., Reyes, T. F., Li, R., Kuhnert, F., Han, X., Yuan, J., Chiou, S., Brettman, A. D., Daly, L., Corney, D. C., Cheshier, S. H., Shortliffe, L. D., Wu, X., Snyder, M., Chan, P., Giffard, R. G., Chang, H. Y., Andreasson, K., Kuo, C. J. 2017; 23 (4): 450-?

  Abstract

  Although blood-brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt-β-catenin signaling. Constitutive activation of Wnt-β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

  View details for DOI 10.1038/nm.4309

  View details for PubMedID 28288111

• DEVELOPMENT AND EVALUATION OF A NEW HIGHLY SPECIFIC TREM1-SPECIFIC PET TRACER FOR IMAGING MALADAPTIVE INFLAMMATION Johnson, E. M., Mayer, A., Wang, Q., Tsai, C., Mehta, S., Habte, B., Ilovich, O., Massoud, T. F., Andreasson, K. I., James, M. L. WILEY. 2017: 15

  View details for Web of Science ID 000399327600035

• Anti-Inflammatory and Neuroprotective Effects of PGE2 EP4 Signaling in Models of Parkinson's Disease. Journal of neuroimmune pharmacology Pradhan, S. S., Salinas, K., Garduno, A. C., Johansson, J. U., Wang, Q., Manning-Bog, A., Andreasson, K. I. 2016: -?

  Abstract

  Inflammation is a ubiquitous factor accompanying normal aging and neurodegeneration, and recent studies indicate a major contribution of inducible cyclooxygenase (COX-2) and its downstream prostaglandin signaling pathways in modulating neuroinflammatory responses and neuronal function. We have previously shown that the prostaglandin PGE2 receptor EP4 suppresses innate immune responses in models of systemic inflammation. Here we investigated the role of the EP4 receptor in models of Parkinson's disease (PD). Systemic co-administration of the EP4 agonist ONO-AE1-329 with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prevented loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) without significant changes in glial activation, suggesting a potent neuroprotective effect of EP4 signaling in this acute model of DA neuronal loss. Cell-specific conditional ablation of EP4 in Cd11bCre;EP4(lox/lox) mice exacerbated MPTP-associated glial activation and T-cell infiltration in SNpc, consistent with anti-inflammatory functions of microglial EP4 signaling. In vitro, in primary microglia stimulated with oligomeric α-synuclein, EP4 receptor activation suppressed generation of pro-inflammatory and oxidative stress factors. Taken together, these findings suggest a dual neuroprotective and anti-inflammatory mechanism of action by the EP4 receptor in models of PD.

  View details for PubMedID 27734267

• Myeloid Cell Prostaglandin E-2 Receptor EP4 Modulates Cytokine Production but Not Atherogenesis in a Mouse Model of Type 1 Diabetes PLOS ONE Vallerie, S. N., Kramer, F., Barnhart, S., Kanter, J. E., Breyer, R. M., Andreasson, K. I., Bornfeldt, K. E. 2016; 11 (6)

  Abstract

  Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E2 (PGE2) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In myeloid cells, a key cell type in atherosclerosis, PGE2 acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE2-mediated EP4 signaling specifically in myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial myeloid cell accumulation, we generated a myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between myeloid cell EP4, inflammatory phenotypes of myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE2 increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis.

  View details for DOI 10.1371/journal.pone.0158316

  View details for Web of Science ID 000378858900053

  View details for PubMedID 27351842

  View details for PubMedCentralID PMC4924840

• Untangling the Web: Toxic and Protective Effects of Neuroinflammation and PGE(2) Signaling in Alzheimer's Disease ACS CHEMICAL NEUROSCIENCE Woodling, N. S., Andreasson, K. I. 2016; 7 (4): 454-463

  Abstract

  The neuroinflammatory response has received increasing attention as a key factor in the pathogenesis of Alzheimer's disease (AD). Microglia, the innate immune cells and resident phagocytes of the brain, respond to accumulating Aβ peptides by generating a nonresolving inflammatory response. While this response can clear Aβ peptides from the nervous system in some settings, its failure to do so in AD accelerates synaptic injury, neuronal loss, and cognitive decline. The complex molecular components of this response are beginning to be unraveled, with identification of both damaging and protective roles for individual components of the neuroinflammatory response. Even within one molecular pathway, contrasting effects are often present. As one example, recent studies of the inflammatory cyclooxygenase-prostaglandin pathway have revealed both beneficial and detrimental effects dependent on the disease context, cell type, and downstream signaling pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenases, are associated with reduced AD risk when taken by cognitively normal populations, but additional clinical and mouse model studies have added complexities and caveats to this finding. Downstream of cyclooxygenase activity, prostaglandin E2 signaling exerts both damaging pro-inflammatory and protective anti-inflammatory effects through actions of specific E-prostanoid G-protein coupled receptors on specific cell types. These complexities underscore the need for careful study of individual components of the neuroinflammatory response to better understand their contribution to AD pathogenesis and progression.

  View details for DOI 10.1021/acschemneuro.6b00016

  View details for Web of Science ID 000374812300007

  View details for PubMedID 26979823

• Microarray analysis of the in vivo response of microglia to Aß peptides in mice with conditional deletion of the prostaglandin EP2 receptor. Genomics data Johansson, J. U., Woodling, N. S., Brown, H. D., Wang, Q., Andreasson, K. I. 2015; 5: 268-271

  Abstract

  Amyloid-β (Aβ) peptides accumulate in the brains of patients with Alzheimer's disease (AD), where they generate a persistent inflammatory response from microglia, the innate immune cells of the brain. The immune modulatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies(1) and in transgenic rodent models of AD(2, 3). PGE2 signals through four G-protein-coupled receptors, including the EP2 receptor that has been investigated for its role in mediating the inflammatory and phagocytic responses to Aβ(4). To identify transcriptional differences in microglia lacking the EP2 receptor, we examined mice with EP2 conditionally deleted in Cd11b-expressing immune cells. We injected Aβ peptides or saline vehicle into the brains of adult mice, isolated primary microglia, and analyzed RNA expression by microarray. The resulting datasets were analyzed in two studies(5, 6), one describing the basal status of microglia with or without EP2 deletion, and the second study analyzing the microglial response to Aβ. Here we describe in detail the experimental design and data analyses. The raw data from these studies are deposited in GEO, accession GSE57181 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57181).

  View details for PubMedID 26251825

• Signaling in Models of Alzheimer's Disease. Current immunology reviews Johansson, J. U., Woodling, N. S., Shi, J., Andreasson, K. I. 2015; 11 (2): 125-131

  Abstract

  The inflammatory response is a fundamental driving force in the pathogenesis of Alzheimer's disease (AD). In the setting of accumulating immunogenic Aß peptide assemblies, microglia, the innate immune cells of the brain, generate a non-resolving immune response and fail to adequately clear accumulating Aß peptides, accelerating neuronal and synaptic injury. Pathological, biomarker, and imaging studies point to a prominent role of the innate immune response in AD development, and the molecular components of this response are beginning to be unraveled. The inflammatory cyclooxygenase-PGE2 pathway is implicated in pre-clinical development of AD, both in epidemiology of normal aging populations and in transgenic mouse models of Familial AD. The cyclooxygenase-PGE2 pathway modulates the inflammatory response to accumulating Aß peptides through actions of specific E-prostanoid G-protein coupled receptors.

  View details for DOI 10.2174/1573395511666150707181414

  View details for PubMedID 28413375

• Through-skull fluorescence imaging of the brain in a new near-infrared window NATURE PHOTONICS Hong, G., Diao, S., Chang, J., Antaris, A. L., Chen, C., Zhang, B., Zhao, S., Atochin, D. N., Huang, P. L., Andreasson, K. I., Kuo, C. J., Dai, H. 2014; 8 (9): 723-730

  Abstract

  To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography with limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400-900 nm) is an alternative but currently requires craniotomy, cranial windows and skull thinning techniques, and the penetration depth is limited to 1-2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3-1.4 micrometre near-infrared window. Reduced photon scattering in this spectral region allows fluorescence imaging reaching a depth of >2 mm in mouse brain with sub-10 micrometre resolution. An imaging rate of ~5.3 frames/s allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of blood flow anomaly in a mouse middle cerebral artery occlusion stroke model.

  View details for DOI 10.1038/NPHOTON.2014.166

  View details for Web of Science ID 000342600100016

  View details for PubMedCentralID PMC5026222

• Through-skull fluorescence imaging of the brain in a new near-infrared window. Nature photonics Hong, G., Diao, S., Chang, J., Antaris, A. L., Chen, C., Zhang, B., Zhao, S., Atochin, D. N., Huang, P. L., Andreasson, K. I., Kuo, C. J., Dai, H. 2014; 8 (9): 723-730

  Abstract

  To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography with limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400-900 nm) is an alternative but currently requires craniotomy, cranial windows and skull thinning techniques, and the penetration depth is limited to 1-2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3-1.4 micrometre near-infrared window. Reduced photon scattering in this spectral region allows fluorescence imaging reaching a depth of >2 mm in mouse brain with sub-10 micrometre resolution. An imaging rate of ~5.3 frames/s allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of blood flow anomaly in a mouse middle cerebral artery occlusion stroke model.

  View details for DOI 10.1038/nphoton.2014.166

  View details for PubMedID 27642366

  View details for PubMedCentralID PMC5026222

• Protection by vascular prostaglandin E-2 signaling in hypoxic-ischemic encephalopathy EXPERIMENTAL NEUROLOGY Taniguchi, H., Anacker, C., Wang, Q., Andreasson, K. 2014; 255: 30-37

  Abstract

  Hypoxic-ischemic encephalopathy (HIE) in neonates is a leading cause of neurological impairment. Significant progress has been achieved investigating the pathologic contributions of excitotoxicity, oxidative stress, and neuroinflammation to cerebral injury in HIE. Less extensively investigated has been the contribution of vascular dysfunction, and whether modulation of cerebral perfusion may improve HIE outcome. Here, we investigated the function of the prostaglandin E2 (PGE2) EP4 receptor, a vasoactive Gαs-protein coupled receptor (GPCR), in rodent models of neonatal HIE. The function of PGE2 signaling through the EP4 receptor was investigated using pharmacological and conditional knockout genetic strategies in vivo in rodent models of HIE. Pharmacologic activation of the EP4 receptor with a selective agonist was significantly cerebroprotective both acutely and after 7days. Measurement of cerebral perfusion during and after hypoxia-ischemia demonstrated that EP4 receptor activation improved cerebral perfusion in both the contralateral and ipsilateral hypoxic-ischemic hemispheres. To test whether vascular EP4 signaling exerted a critical function in HIE injury, cell specific conditional knockout mouse pups were generated in which endothelial EP4 receptor was selectively deleted postnatally. VE-Cadherin Cre-ER(T2);EP4(lox/lox) pups demonstrated significant increases in cerebral injury as compared to VE-Cadherin Cre-ER(T2);EP4(+/+) control littermates, indicating that endothelial EP4 signaling is protective in HIE. Our findings identify vascular PGE2 signaling through its EP4 receptor as protective in HIE. Given the pharmacologic accessibility of endothelial EP4 GPCRs, these data support further investigation into novel approaches to target cerebral perfusion in neonatal HIE.

  View details for DOI 10.1016/j.expneurol.2014.02.012

  View details for Web of Science ID 000335287600004

  View details for PubMedID 24560715

  View details for PubMedCentralID PMC4024460

• Suppression of Alzheimer-Associated Inflammation by Microglial Prostaglandin-E-2 EP4 Receptor Signaling JOURNAL OF NEUROSCIENCE Woodling, N. S., Wang, Q., Priyam, P. G., Larkin, P., Shi, J., Johansson, J. U., Zagol-Ikapitte, I., Boutaud, O., Andreasson, K. I. 2014; 34 (17): 5882-5894

  Abstract

  A persistent and nonresolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aβ deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.

  View details for DOI 10.1523/JNEUROSCI.0410-14.2014

  View details for Web of Science ID 000334929100016

  View details for PubMedID 24760848

  View details for PubMedCentralID PMC3996215

• Suppression of Inflammation with Conditional Deletion of the Prostaglandin E-2 EP2 Receptor in Macrophages and Brain Microglia JOURNAL OF NEUROSCIENCE Johansson, J. U., Pradhan, S., Lokteva, L. A., Woodling, N. S., Ko, N., Brown, H. D., Wang, Q., Loh, C., Cekanaviciute, E., Buckwalter, M., Manning-Bog, A. B., Andreasson, K. I. 2013; 33 (40): 16016-16032

  Abstract

  Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2(lox/lox) mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.

  View details for DOI 10.1523/JNEUROSCI.2203-13.2013

  View details for PubMedID 24089506

• Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease. Experimental neurology Pradhan, S., Andreasson, K. 2013; 241: 148-155

  Abstract

  Parkinson's disease (PD) is a progressive neurodegenerative disorder with three cardinal features of pathology: 1. Aggregation of α-synuclein into intraneuronal structures called Lewy bodies and Lewy neurites. 2. Dysregulated immune activation in the substantia nigra (SN). 3. Degeneration of dopaminergic neurons in the nigrostriatal circuit. The largely correlative nature of evidence in humans has precluded a decisive verdict on the relationship between α-synuclein pathology, inflammation, and neuronal damage. Furthermore, it is unclear whether inflammation plays a role in the early prodromal stages of PD before neuronal damage has occurred and Parkinsonian motor symptoms become apparent. To gain insight into the interaction between the inflammatory response and the development of neuronal pathology in PD, Watson et al. characterized neuroinflammation in a wild-type α-synuclein overexpressing mouse model of prodromal PD. They demonstrate, for the first time, the existence of early and sustained microglial mediated innate inflammation that precedes damage to the nigrostriatal circuit. Additionally they observe the spread of inflammation from the striatum to the SN. This study suggests that early dysregulated inflammation may contribute to progressive nigrostriatal pathology in PD, although the initiating factor that triggers the inflammatory response remains elusive. The novel concept of an early inflammatory response in the development of PD has important implications for preventive and therapeutic strategies for PD.

  View details for DOI 10.1016/j.expneurol.2012.12.008

  View details for PubMedID 23261765

• Investigating the role of prostaglandin E2 mediated neuroinflammation in models of Parkinsonism 11th International Congress of Neuroimmunology (ISNI) Pradhan, S., Johansson, J., Wang, Q., Ko, N., Manning-Bog, A., Andreasson, K. ELSEVIER SCIENCE BV. 2012: 111–12

  View details for Web of Science ID 000312764800300

• Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease ANNALS OF NEUROLOGY Shi, J., Wang, Q., Johansson, J. U., Liang, X., Woodling, N. S., Priyam, P., Loui, T. M., Merchant, M., Breyer, R. M., Montine, T. J., Andreasson, K. 2012; 72 (5): 788-798

  Abstract

  There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1ΔE9 mice.Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.

  View details for DOI 10.1002/ana.23677

  View details for Web of Science ID 000312940300017

  View details for PubMedID 22915243

  View details for PubMedCentralID PMC3509238

• Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of beta-Amyloid in T(H)1 and T(H)17 Versions of Experimental Autoimmune Encephalomyelitis SCIENCE TRANSLATIONAL MEDICINE Grant, J. L., Ghosn, E. E., Axtell, R. C., Herges, K., Kuipers, H. F., Woodling, N. S., Andreasson, K., Herzenberg, L. A., Herzenberg, L. A., Steinman, L. 2012; 4 (145)

  Abstract

  β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

  View details for DOI 10.1126/scitranslmed.3004145

  View details for Web of Science ID 000307159500004

  View details for PubMedID 22855462

• Signaling via the prostaglandin E-2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia JOURNAL OF CLINICAL INVESTIGATION Liang, X., Lin, L., Woodling, N. S., Wang, Q., Anacker, C., Pan, T., Merchant, M., Andreasson, K. 2011; 121 (11): 4362-4371

  Abstract

  Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemia-reperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke.

  View details for DOI 10.1172/JCI46279

  View details for Web of Science ID 000296482700019

  View details for PubMedID 21965326

  View details for PubMedCentralID PMC3204834

• Function of prostaglandin E-2 EP receptors in the acute outcome of rodent hypoxic ischemic encephalopathy NEUROSCIENCE LETTERS Taniguchi, H., Anacker, C., Suarez-Mier, G. B., Wang, Q., Andreasson, K. 2011; 504 (3): 185-190

  Abstract

  Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of severe and permanent neurologic disability after birth. The inducible cyclooxygenase COX-2, which along with COX-1 catalyzes the first committed step in prostaglandin (PG) synthesis, elicits significant brain injury in models of cerebral ischemia; however its downstream PG receptor pathways trigger both toxic and paradoxically protective effects. Here, we investigated the function of PGE(2) E-prostanoid (EP) receptors in the acute outcome of hypoxic-ischemic (HI) injury in the neonatal rat. We determined the temporal and cellular expression patterns of the EP1-4 receptors before and after HIE and tested whether modulation of EP1-4 receptor function could protect against cerebral injury acutely after HIE. All four EP receptors were expressed in forebrain neurons and were induced in endothelial cells after HIE. Inhibition of EP1 signaling with the selective antagonist SC-51089 or co-activation of EP2-4 receptors with the agonist misoprostol significantly reduced HIE cerebral injury 24 h after injury. These receptor ligands also protected brain endothelial cells subjected to oxygen glucose deprivation, suggesting that activation of EP receptor signaling is directly cytoprotective. These data indicate that the G-protein coupled EP receptors may be amenable to pharmacologic targeting in the acute setting of neonatal HIE.

  View details for DOI 10.1016/j.neulet.2011.09.005

  View details for Web of Science ID 000296951400001

  View details for PubMedID 21939736

  View details for PubMedCentralID PMC3210938

• Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold MOLECULAR NEURODEGENERATION Grabrucker, A. M., Schmeisser, M. J., Udvardi, P. T., Arons, M., Schoen, M., Woodling, N. S., Andreasson, K. I., Hof, P. R., Buxbaum, J. D., Garner, C. C., Boeckers, T. M. 2011; 6

  Abstract

  Memory deficits in Alzheimer's disease (AD) manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/Shank3 scaffold assembly within the PSD is Zn2+-dependent and that the amyloid beta protein (Aβ) is able to bind Zn2+, we hypothesize that sequestration of Zn2+ ions by Aβ contributes to ProSAP/Shank platform malformation.To test this hypothesis, we designed multiple in vitro and in vivo assays demonstrating ProSAP/Shank dysregulation in rat hippocampal cultures following Aβ oligomer accumulation. These changes were independent from alterations on ProSAP/Shank transcriptional level. However, application of soluble Aβ prevented association of Zn2+ ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn2+ clusters within dendrites. Zn2+ supplementation or saturation of Aβ with Zn2+ ions prior to cell treatment was able to counter the effects induced by Aβ on synapse density and ProSAP2/Shank3 levels at the PSD. Interestingly, intracellular Zn2+ levels in APP-PS1 mice and human AD hippocampus are reduced along with a reduction in synapse density and synaptic ProSAP2/Shank3 and Shank1 protein levels.We conclude that sequestration of Zn2+ ions by Aβ significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature) synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons.

  View details for DOI 10.1186/1750-1326-6-65

  View details for Web of Science ID 000295832100001

  View details for PubMedID 21939532

  View details for PubMedCentralID PMC3189132

• The Prostaglandin E-2 E-Prostanoid 4 Receptor Exerts Anti-Inflammatory Effects in Brain Innate Immunity JOURNAL OF IMMUNOLOGY Shi, J., Johansson, J., Woodling, N. S., Wang, Q., Montine, T. J., Andreasson, K. 2010; 184 (12): 7207-7218

  Abstract

  Peripheral inflammation leads to immune responses in brain characterized by microglial activation, elaboration of proinflammatory cytokines and reactive oxygen species, and secondary neuronal injury. The inducible cyclooxygenase (COX), COX-2, mediates a significant component of this response in brain via downstream proinflammatory PG signaling. In this study, we investigated the function of the PGE2 E-prostanoid (EP) 4 receptor in the CNS innate immune response to the bacterial endotoxin LPS. We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced proinflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and I-kappaB kinase phosphorylation and decreased nuclear translocation of p65 and p50 NF-kappaB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and proinflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced proinflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrated adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific PG signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.

  View details for DOI 10.4049/jimmunol.0903487

  View details for Web of Science ID 000278516700071

  View details for PubMedID 20483760

  View details for PubMedCentralID PMC3103215

• Prostaglandin signalling in cerebral ischaemia BRITISH JOURNAL OF PHARMACOLOGY Andreasson, K. 2010; 160 (4): 844-846

  Abstract

  The inducible cyclooxygenase COX-2 exerts neurotoxic effects in a wide spectrum of neurological disease models, including models of cerebral ischaemia and chronic neurodegeneration. As COX-1 and COX-2 catalyse the first committed step in prostaglandin synthesis, recent efforts have focused on identifying the downstream prostaglandin signalling pathways responsible for mediating the toxic effect of COX-2. Recent studies in models of in vitro excitotoxicity or hypoxia demonstrate that certain prostaglandin receptors mediate toxic effects, but a large number appear to mediate paradoxically protective effects. In vivo studies have begun to confirm initial in vitro findings, with selected prostaglandin receptors eliciting either neurotoxic or protective effects in models of cerebral ischaemia. In the present issue, Ikeda-Matsuo et al. examine the function of the PGE(2) EP3 receptor in a model of transient focal ischaemia and explore its potential signalling through Rho kinase activation.

  View details for DOI 10.1111/j.1476-5381.2010.00715.x

  View details for Web of Science ID 000278032300006

  View details for PubMedID 20590583

  View details for PubMedCentralID PMC2935992

• Emerging roles of PGE(2) receptors in models of neurological disease PROSTAGLANDINS & OTHER LIPID MEDIATORS Andreasson, K. 2010; 91 (3-4): 104-112

  Abstract

  This review presents an overview of the emerging field of prostaglandin signaling in neurological diseases, focusing on PGE(2) signaling through its four E-prostanoid (EP) receptors. A large number of studies have demonstrated a neurotoxic function of the inducible cyclooxygenase COX-2 in a broad spectrum of neurological disease models in the central nervous system (CNS), from models of cerebral ischemia to models of neurodegeneration and inflammation. Since COX-1 and COX-2 catalyze the first committed step in prostaglandin synthesis, an effort is underway to identify the downstream prostaglandin signaling pathways that mediate the toxic effect of COX-2. Recent epidemiologic studies demonstrate that chronic COX-2 inhibition can produce adverse cerebrovascular and cardiovascular effects, indicating that some prostaglandin signaling pathways are beneficial. Consistent with this concept, recent studies demonstrate that in the CNS, specific prostaglandin receptor signaling pathways mediate toxic effects in brain but a larger number appear to mediate paradoxically protective effects. Further complexity is emerging, as exemplified by the PGE(2) EP2 receptor, where cerebroprotective or toxic effects of a particular prostaglandin signaling pathway can differ depending on the context of cerebral injury, for example, in excitotoxicity/hypoxia paradigms versus inflammatory-mediated secondary neurotoxicity. The divergent effects of prostaglandin receptor signaling will likely depend on distinct patterns and dynamics of receptor expression in neurons, endothelial cells, and glia and the specific ways in which these cell types participate in particular models of neurological injury.

  View details for DOI 10.1016/j.prostaglandins.2009.04.003

  View details for Web of Science ID 000277722600006

  View details for PubMedID 19808012

  View details for PubMedCentralID PMC2846228

• The organotypic hippocampal slice culture model for examining neuronal injury. Journal of visualized experiments : JoVE Wang, Q., Andreasson, K. 2010

  Abstract

  Organotypic hippocampal slice culture is an in vitro method to examine mechanisms of neuronal injury in which the basic architecture and composition of the hippocampus is relatively preserved (1). The organotypic culture system allows for the examination of neuronal, astrocytic and microglial effects, but as an ex vivo preparation, does not address effects of blood flow, or recruitment of peripheral inflammatory cells. To that end, this culture method is frequently used to examine excitotoxic and hypoxic injury to pyramidal neurons of the hippocampus, but has also been used to examine the inflammatory response. Herein we describe the methods for generating hippocampal slice cultures from postnatal rodent brain, administering toxic stimuli to induce neuronal injury, and assaying and quantifying hippocampal neuronal death.

  View details for DOI 10.3791/2106

  View details for PubMedID 21085096

  View details for PubMedCentralID PMC3185629

• Prostaglandin E-2-EP4 receptor agonist protects neonatal brain from hypoxia-ischemia Taniguchi, H., Anacker, C., Liang, X., Wang, Q., Sabar, F., Andreasson, K. NATURE PUBLISHING GROUP. 2009: S541

  View details for Web of Science ID 000270329900662

• Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor EXPERIMENTAL NEUROLOGY Savonenko, A., Munoz, P., Melnikova, T., Wang, Q., Liang, X., Breyer, R. M., Montine, T. J., Kirkwood, A., Andreasson, K. 2009; 217 (1): 63-73

  Abstract

  Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.

  View details for DOI 10.1016/j.expneurol.2009.01.016

  View details for Web of Science ID 000265859000009

  View details for PubMedID 19416671

  View details for PubMedCentralID PMC2720138

• Small Molecule, Non-Peptide p75(NTR) Ligands Inhibit A beta-Induced Neurodegeneration and Synaptic Impairment PLOS ONE Yang, T., Knowles, J. K., Lu, Q., Zhang, H., Arancio, O., Moore, L. A., Chang, T., Wang, Q., Andreasson, K., Rajadas, J., Fuller, G. G., Xie, Y., Massa, S. M., Longo, F. M. 2008; 3 (11)

  Abstract

  The p75 neurotrophin receptor (p75(NTR)) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75(NTR) ligands found to promote survival signaling might prevent Abeta-induced degeneration and synaptic dysfunction. These ligands inhibited Abeta-induced neuritic dystrophy, death of cultured neurons and Abeta-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Abeta-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3beta and c-Jun, and tau phosphorylation, and prevented Abeta-induced inactivation of AKT and CREB. Finally, a p75(NTR) ligand blocked Abeta-induced hippocampal LTP impairment. These studies support an extensive intersection between p75(NTR) signaling and Abeta pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Abeta-induced neuronal dystrophy and death.

  View details for DOI 10.1371/journal.pone.0003604

  View details for Web of Science ID 000265134200003

  View details for PubMedID 18978948

  View details for PubMedCentralID PMC2575383

• The prostaglandin E-2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis ANNALS OF NEUROLOGY Liang, X., Wang, Q., Shi, J., Lokteva, L., Breyer, R. M., Montine, T. J., Andreasson, K. 2008; 64 (3): 304-314

  Abstract

  Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E(2) EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS.We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model.EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E(2)EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1DeltaE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes.These data suggest that prostaglandin E(2) signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease.

  View details for DOI 10.1002/ana.21437

  View details for Web of Science ID 000259681700013

  View details for PubMedID 18825663

  View details for PubMedCentralID PMC2766522

• Misoprostol, an anti-ulcer agent and PGE(2) receptor agonist, protects against cerebral ischemia NEUROSCIENCE LETTERS Li, J., Liang, X., Wang, Q., Breyer, R. M., McCullough, L., Andreasson, K. 2008; 438 (2): 210-215

  Abstract

  Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE(2) receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE(2) EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion-reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2h after MCAO, resulted in significant rescue of infarct volume at 24 and 72h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3-/- mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3-/- mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE(2) EP2 and/or EP4 receptors.

  View details for DOI 10.1016/j.neulet.2008.04.054

  View details for Web of Science ID 000257276900017

  View details for PubMedID 18472336

  View details for PubMedCentralID PMC2621308

• COX-2 oxidative metabolism of endocannabinoids augments hippocampal synaptic plasticity MOLECULAR AND CELLULAR NEUROSCIENCE Yang, H., Zhang, J., Andreasson, K., Chen, C. 2008; 37 (4): 682-695

  Abstract

  Endocannabinoids (eCBs) are important endogenous lipid mediators in synaptic transmission and plasticity and are oxygenated by cyclooxygenase-2 (COX-2) to form new types of prostaglandins. However, little is known about whether COX-2 oxidative metabolism of eCBs and their metabolites alter synaptic signaling. Here we demonstrate that increased COX-2 expression significantly enhances basal synaptic transmission and augments long-term potentiation (LTP) in the mouse hippocampus. This augmentation was inhibited in the presence of a selective COX-2 inhibitor or with deletion of the COX-2 gene. The CB(1) receptor-mediated depolarization-induced suppression of inhibition (DSI) was diminished when COX-2 expression was increased either with lipopolysaccharide (LPS) stimulation or transgenic neuronal over-expression of COX-2. Conversely, DSI was potentiated when COX-2 activity was pharmacologically or genetically inhibited. Interestingly, COX-2 oxidative metabolites of eCBs elevated LTP, an effect opposite to that of their parent molecules 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA). In addition, the ERK/MAPK and IP(3) pathways were found to mediate PGE(2)-G-induced enhancement of LTP. Our results indicate that COX-2 oxidative metabolism of eCBs is an important signaling pathway in modulation of synaptic transmission and plasticity.

  View details for DOI 10.1016/j.mcn.2007.12.019

  View details for Web of Science ID 000254905300005

  View details for PubMedID 18295507

  View details for PubMedCentralID PMC2396786

• Function of prostaglandin receptors in models of neurological disease Andreasson, K. I. BLACKWELL PUBLISHING. 2008: 12–13

  View details for Web of Science ID 000252815800026

• The hypoxic-ischemic encephalopathy model of perinatal ischemia. Journal of visualized experiments : JoVE Taniguchi, H., Andreasson, K. 2008

  Abstract

  Hypoxic-Ischemic Encephalopathy (HIE) is the consequence of systemic asphyxia occurring at birth. Twenty five percent of neonates with HIE develop severe and permanent neuropsychological sequelae, including mental retardation, cerebral palsy, and epilepsy. The outcomes of HIE are devastating and permanent, making it critical to identify and develop therapeutic strategies to reduce brain injury in newborns with HIE. To that end, the neonatal rat model for hypoxic-ischemic brain injury has been developed to model this human condition. The HIE model was first validated by Vannucci et al and has since been extensively used to identify mechanisms of brain injury resulting from perinatal hypoxia-ischemia and to test potential therapeutic interventions. The HIE model is a two step process and involves the ligation of the left common carotid artery followed by exposure to a hypoxic environment. Cerebral blood flow (CBF) in the hemisphere ipsilateral to the ligated carotid artery does not decrease because of the collateral blood flow via the circle of Willis; however with lower oxygen tension, the CBF in the ipsilateral hemisphere decreases significantly and results in unilateral ischemic injury. The use of 2,3,5-triphenyltetrazolium chloride (TTC) to stain and identify ischemic brain tissue was originally developed for adult models of rodent cerebral ischemia, and is used to evaluate the extent of cerebral infarctin at early time points up to 72 hours after the ischemic event. In this video, we demonstrate the hypoxic-ischemic injury model in postnatal rat brain and the evaluation of the infarct size using TTC staining.

  View details for DOI 10.3791/955

  View details for PubMedID 19066530

  View details for PubMedCentralID PMC2953967

• Divergent effects of prostaglandin receptor signaling on neuronal survival NEUROSCIENCE LETTERS Wu, L., Wang, Q., Liang, X., Andreasson, K. 2007; 421 (3): 253-258

  Abstract

  Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protect neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD(2), PGI(2), and PGF(2alpha) receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI(2) and TXA(2) receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl-d-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.

  View details for DOI 10.1016/j.neulet.2007.05.055

  View details for Web of Science ID 000248152100014

  View details for PubMedID 17574754

  View details for PubMedCentralID PMC2680717

• Function of COX-2 and prostaglandins in neurological disease International Workshop on Brain Uptake and Utilization of Fatty Acids, Lipids and Lipoproteins Liang, X., Wu, L., Wang, Q., Hand, T., Bilak, M., McCullough, L., Andreasson, K. HUMANA PRESS INC. 2007: 94–99

  Abstract

  Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease. Inhibition of COX-2 activity, either genetically or pharmacologically, has been shown to be neuroprotective in rodent models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces inflammation and amyloid accumulation in murine transgenic models of Familial Alzheimer's disease, and the use of NSAIDs decreases the risk of developing Alzheimer's disease in healthy aging populations. COX-mediated neuronal injury is presumed be due to downstream effects of one or more prostaglandin products including PGE2, PGD2, PGF2alpha, PGI2 (prostacylin) and TXA2 (thromboxane) that effect cellular changes through activation of specific prostaglandin receptor subtypes and second messenger systems. In this proceeding, we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective, when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity. Conversely, in the context of an inflammatory stimulus, the EP2 receptor enhances neuronal injury. These findings argue for an additional level of complexity in the prostaglandin response in neurological disease.

  View details for DOI 10.1007/s12031-007-0058-8

  View details for Web of Science ID 000249670800015

  View details for PubMedID 17901552

• Trial of celecoxib in amyotrophic lateral sclerosis ANNALS OF NEUROLOGY Cudkowicz, M. E., Shefner, J. M., Schoenfeld, D. A., Zhang, H., Andreasson, K. I., Rothstein, J. D., Drachman, D. B. 2006; 60 (1): 22-31

  Abstract

  To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS).A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates.Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment.At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.

  View details for DOI 10.1002/ana.20903

  View details for Web of Science ID 000238825500008

  View details for PubMedID 16802291

• Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern NEUROSCIENCE Melnikova, T., Savonenko, A., Wang, Q., Liang, X., Hand, T., Wu, L., Kaufmann, W. E., Vehmas, A., Andreasson, K. I. 2006; 141 (3): 1149-1162

  Abstract

  Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.

  View details for DOI 10.1016/j.neuroscience.2006.05.001

  View details for Web of Science ID 000239822800006

  View details for PubMedID 16753269

• Deletion of the prostaglandin E-2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer's disease JOURNAL OF NEUROSCIENCE Liang, X. B., Wang, Q., Hand, T., Wu, L. J., Breyer, R. M., Montine, T. J., Andreasson, K. 2005; 25 (44): 10180-10187

  Abstract

  Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E2 (PGE2) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE2 EP2 receptor in the APPSwe-PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-beta (Abeta) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C-terminal fragments, the product of beta-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased Abeta peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

  View details for DOI 10.1523/JNEUROSCI.3591-05.2005

  View details for Web of Science ID 000232988500015

  View details for PubMedID 16267225

• Sex differences in cell death ANNALS OF NEUROLOGY Li, H., Pin, S., Zeng, Z. Y., Wang, M. M., Andreasson, K. A., McCullough, L. D. 2005; 58 (2): 317-321

  Abstract

  Female patients experience substantial neuroprotection after experimental stroke compared with male patients, a finding attributed to the protective effects of gonadal hormones. This study examined the response of male- and female-derived organotypic hippocampal slices to oxidative and excitotoxic injury. Both oxygen and glucose deprivation and N-methyl-D-aspartic acid exposure led to neuronal death; however, female-derived cultures sustained less injury than male-derived cultures. Cell death after oxygen and glucose deprivation was ameliorated in male cultures, but not female cultures, by the addition of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor. These studies have relevance to researchers investigating neuroprotective agents in mixed sex experiments.

  View details for DOI 10.1002/ana.20538

  View details for Web of Science ID 000230856000017

  View details for PubMedID 15988750

• Prostaglandin H-2-derived adducts of proteins correlate with Alzheimer's disease severity JOURNAL OF NEUROCHEMISTRY Zagol-Ikapitte, I., Masterson, T. S., Amarnath, V., Montine, T. J., Andreasson, K. I., Boutaud, O., Oates, J. A. 2005; 94 (4): 1140-1145

  Abstract

  The formation of cyclooxygenase-derived lipid adducts of protein in brains of patients who had Alzheimer's disease has been investigated. The enzymatic product of the cyclooxygenases, prostaglandin H2, rearranges in part to highly reactive gamma-ketoaldehydes, levuglandin (LG) E(2) and LGD(2). These gamma-ketoaldehydes react with free amines on proteins to yield a covalent adduct. Utilizing analysis of the levuglandinyl-lysine adducts by liquid chromatography-tandem mass spectrometry, we now find that this post-translational modification is increased significantly in the hippocampus in Alzheimer's disease. The magnitude of the increase correlates with the pathological evidence of severity.

  View details for DOI 10.1111/j.1471-4159.2005.03264.x

  View details for Web of Science ID 000230888200026

  View details for PubMedID 15992375

• Neuroprotection by the PGE(2) EP2 receptor in permanent focal cerebral ischemia ANNALS OF NEUROLOGY Liu, D., Wu, L. J., Breyer, R., Mattson, M. P., Andreasson, K. 2005; 57 (5): 758-761

  Abstract

  Recent studies suggest a neuroprotective function of the PGE2 EP2 receptor in excitotoxic neuronal injury. The function of the EP2 receptor was examined at time points after excitotoxicity in an organotypic hippocampal model of N-methyl-D-aspartate (NMDA) challenge and in a permanent model of focal forebrain ischemia. Activation of EP2 led to significant neuroprotection in hippocampal slices up to 3 hours after a toxic NMDA stimulus. Genetic deletion of EP2 resulted in a marked increase in stroke volume in the permanent middle cerebral artery occlusion model. These findings support further investigation into therapeutic strategies targeting the EP2 receptor in stroke.

  View details for DOI 10.1002/ana.20461

  View details for Web of Science ID 000228937300021

  View details for PubMedID 15852374

• Cyclooxygenase-dependent lipid-modification of brain proteins BRAIN PATHOLOGY Boutaud, O., Andreasson, K. I., Zagol-Ikapitte, I., Oates, J. 2005; 15 (2): 139-142

  Abstract

  Substantial evidence indicates that both beta-amyloid and cyclooxygenase activity contribute to the pathogenesis of Alzheimer disease. The immediate product of the cyclooxygenases, prostaglandin H2, rapidly rearranges in aqueous solution, with approximately 20% being converted to levuglandins E2 and D2. These gamma-ketoaldehydes are highly reactive and rapidly adduct to accessible amine groups on macromolecules, particularly the epsilon-amine of lysine residues on proteins. The immediate LG-lysine adducts are themselves reactive, and can covalently crosslink proteins. PGH2, acting via LGs, accelerates the formation of the type of oligomers of amyloid beta that has been associated with neurotoxicity. In this review, we discuss the cyclooxygenase-dependent lipid-modification of proteins by levuglandins in vitro, in cells in culture and in vivo in transgenic mice over-expressing COX in the brain.

  View details for Web of Science ID 000228514500007

  View details for PubMedID 15912886

• Prostaglandin D-2 mediates neuronal protection via the DP1 receptor JOURNAL OF NEUROCHEMISTRY Liang, X. B., Wu, L. J., Hand, T., Andreasson, K. 2005; 92 (3): 477-486

  Abstract

  Cyclo-oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE(2), PGD(2), PGF(2alpha), PGI(2) and thomboxane A(2). Expression and enzymatic activity of COX-2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX-2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD(2) and its two receptors DP1 and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD(2) is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein-coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD(2) potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1-selective agonist BW245C but not by the PGD(2) metabolite 15d-PGJ(2), suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD(2), indicating that PGD(2)-mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD(2) DP1 receptor protects against excitotoxic injury in a cAMP-dependent manner, consistent with recent studies of PGE(2) receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.

  View details for DOI 10.1111/j.1471-4159.2004.02870.x

  View details for Web of Science ID 000226401900005

  View details for PubMedID 15659218

• PGE(2) receptors rescue motor neurons in a model of amyotrophic lateral sclerosis ANNALS OF NEUROLOGY Bilak, M., Wu, L. J., Wang, Q., Haughey, N., Conant, K., Hillaire, C. S., Andreasson, K. 2004; 56 (2): 240-248

  Abstract

  Recent studies suggest that the inducible isoform of cyclooxygenase, COX-2, promotes motor neuron loss in rodent models of ALS. We investigated the effects of PGE2, a principal downstream prostaglandin product of COX-2 activity, on motor neuron survival in an organotypic culture model of ALS. We find that PGE2 paradoxically protects motor neurons at physiological concentrations in this model. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled E-prostanoid receptors (EP1-EP4) that have divergent effects on cAMP. EP2 and EP3 are dominantly expressed in ventral spinal cord in neurons and astrocytes, and activation of these receptor subtypes individually or in combination also rescued motor neurons. The EP2 receptor is positively coupled to cAMP, and its neuroprotection was mimicked by application of forskolin and blocked by inhibition of PKA, suggesting that its protective effect is mediated by downstream effects of cAMP. Conversely, the EP3 receptor is negatively coupled to cAMP, and its neuroprotective effect was blocked by pertussis toxin, suggesting that its protective effect is dependent on Gi-coupled heterotrimeric signaling. Taken together, these data demonstrate an unexpected neuroprotective effect mediated by PGE2, in which activation of its EP2 and EP3 receptors protected motor neurons from chronic glutamate toxicity.

  View details for DOI 10.1002/ana.20179

  View details for Web of Science ID 000223434700010

  View details for PubMedID 15293276

• Neuroprotective function of the PGE(2) EP2 receptor in cerebral ischemia JOURNAL OF NEUROSCIENCE McCullough, L., Wu, L. J., Haughey, N., Liang, X. B., Hand, T., Wang, Q., Breyer, R. M., Andreasson, K. 2004; 24 (1): 257-268

  Abstract

  The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE2, a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMP-dependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE2 receptor subtype in brain that may provide a target for therapeutic intervention.

  View details for DOI 10.1523/JNEUROSCI.4485-03.2004

  View details for Web of Science ID 000187888700027

  View details for PubMedID 14715958

• Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction 31st Annual Meeting of the Society-for-Neuroscience Dore, S., Otsuka, T., Mito, T., Sugo, N., Hand, T., Wu, L. J., Hurn, P. D., Traystman, R. J., Andreasson, K. WILEY-LISS. 2003: 155–62

  Abstract

  Increases in COX-2 enzymatic activity and prostaglandin production have been associated with neuronal injury in both acute and age-related degenerative neurological diseases. In this study, we tested the effects of increased COX-2 activity in a model of transient focal ischemia using a transgenic mouse model in which human COX-2 is constitutively expressed selectively in neurons of the striatum, cerebral cortex, and hippocampus. These COX-2 transgenic mice harbor elevated levels of PGE(2) that are 10-fold higher than nontransgenic levels. A significant increase in infarct volume was observed after middle cerebral artery occlusion with 4 days of reperfusion in COX-2 transgenic mice as compared with nontransgenic littermates. Pretreatment of nontransgenic mice with the selective COX-2 inhibitor SC58236 resulted in a significant reduction of infarct volume in nontransgenic mice, consistent with previous pharmacological studies. However, transgenic COX-2 mice treated with SC58236 did not show a significant reduction. This suggests that chronic increases in COX-2 expression and enzymatic activity, which can occur in aging and in pathological states characterized by oxidative stress and chronic inflammatory processes, can lead to downstream cellular changes that have a negative impact on neuronal survival in cerebrovascular disease.

  View details for DOI 10.1002/ana.10612

  View details for Web of Science ID 000184352700005

  View details for PubMedID 12891667

• Neuronal overexpression of COX-2 results in dominant production of PGE(2) and altered fever response NEUROMOLECULAR MEDICINE Vidensky, S., Zhang, Y., Hand, T., Goellner, J., Shaffer, A., Isakson, P., Andreasson, K. 2003; 3 (1): 15-27

  Abstract

  Cyclooxygenases catalyze the first committed step in the formation of prostaglandins and thromboxanes from arachidonic acid. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is expressed in brain selectively in neurons of hippocampus, cerebral cortex, amygdala, and hypothalamus. Prostaglandins function in many processes in the CNS, including fever induction, nociception, and learning and memory, and are upregulated in paradigms of excitotoxic brain injury such as stroke and epilepsy. To address the varied functions of COX-2 and its prostaglandin products in brain, we have developed a transgenic mouse model in which COX-2 is selectively overexpressed in neurons of the CNS. COX-2 transgenic mice demonstrate elevated levels of all prostaglandins and thromboxane, albeit with a predominant induction of PGE(2) over other prostaglandins, followed by more modest inductions of PGI(2), and relatively smaller increases in PGF(2alpha),PGD(2), and TxB(2). We also examined whether increased neuronal production of prostaglandins would affect fever induction in response to the bacterial endotoxin lipopolysaccharide. COX-2 induction in brain endothelium has been previously determined to play an important role in fever induction, and we tested whether neuronal expression of COX-2 in hypothalamus also contributed to the febrile response. We found that in mice expressing transgenic COX-2 in anterior hypothalamus, the febrile response was significantly potentiated in transgenic as compared to non-transgenic mice, with an accelerated onset of fever by 1 2 hours after LPS administration, suggesting a role for neuronally derived COX-2 in the fever response.

  View details for Web of Science ID 000181531400002

  View details for PubMedID 12665673

• Role of immediate early gene expression in cortical morphogenesis and plasticity. Results and problems in cell differentiation Andreasson, K. I., Kaufmann, W. E. 2002; 39: 113-137

  Abstract

  During the development of the central nervous system, there is a fundamental requirement for synaptic activity in transforming immature neuronal connections into organized functional circuits (Katz 1996). The molecular mechanisms underlying activity-dependent adaptive changes in neurons are believed to involve regulated cascades of gene expression. Immediate early genes (IEGs) comprise the initial cascade of gene expression responsible for initiating the process of stimulus-induced adaptive change, and were identified initially as transcription factors that were regulated in brain by excitatory synaptic activity. More recently, a class of neuronal immediate early genes has been identified that encodes growth factors, signaling molecules, extracellular matrix and adhesion proteins, and cytoskeletal proteins that are rapidly and transiently expressed in response to glutamatergic neurotransmission. This review focuses on the neuronal immediate early gene (nIEG) response, in particular, the class of "effector" immediate early gene proteins that may directly modify neuronal and synaptic function.

  View details for PubMedID 12353466

• Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice JOURNAL OF NEUROSCIENCE Andreasson, K. I., Savonenko, A., Vidensky, S., Goellner, J. J., Zhang, Y., Shaffer, A., Kaufmann, W. E., Worley, P. F., Isakson, P., Markowska, A. L. 2001; 21 (20): 8198-8209

  Abstract

  The cyclooxygenases catalyze the rate-limiting step in the formation of prostaglandins from arachidonic acid and are the pharmacological targets of (NSAIDs). In brain, cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is selectively expressed in neurons of the cerebral cortex, hippocampus, and amygdala. As an immediate-early gene, COX-2 is dramatically and transiently induced in these neurons in response to NMDA receptor activation. In models of acute excitotoxic neuronal injury, elevated and sustained levels of COX-2 have been shown to promote neuronal apoptosis, indicating that upregulated COX-2 activity is injurious to neurons. COX-2 may also contribute to the development of Alzheimer's disease, for which early administration of NSAIDs is protective against development of the disease. To test the effect of constitutively elevated neuronal COX-2, transgenic mice were generated that overexpressed COX-2 in neurons and produced elevated levels of prostaglandins in brain. In cross-sectional behavioral studies, COX-2 transgenic mice developed an age-dependent deficit in spatial memory at 12 and 20 months but not at 7 months and a deficit in aversive behavior at 20 months of age. These behavioral changes were associated with a parallel age-dependent increase in neuronal apoptosis occurring at 14 and 22 months but not at 8 months of age and astrocytic activation at 24 months of age. These findings suggest that neuronal COX-2 may contribute to the pathophysiology of age-related diseases such as Alzheimer's disease by promoting memory dysfunction, neuronal apoptosis, and astrocytic activation in an age-dependent manner.

  View details for Web of Science ID 000171442000040

  View details for PubMedID 11588192

• Arcadlin is a neural activity-regulated cadherin involved in long term potentiation JOURNAL OF BIOLOGICAL CHEMISTRY Yamagata, K., Andreasson, K. I., Sugiura, H., Maru, E., Dominique, M., Irie, Y., Miki, N., Hayashi, Y., Yoshioka, M., Kaneko, K., Kato, H., Worley, P. F. 1999; 274 (27): 19473-19479

  Abstract

  Neural activity results in long term changes that underlie synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here, we identify a novel cadherin molecule Arcadlin (activity-regulated cadherin-like protein). arcadlin mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by N-methyl-D-aspartate-dependent synaptic activity in long term potentiation. The extracellular domain of Arcadlin is most homologous to protocadherin-8; however, the cytoplasmic region is distinct from that of any cadherin family member. Arcadlin protein is expressed at the synapses and shows a homophilic binding activity in a Ca2+-dependent manner. Furthermore, application of Arcadlin antibody reduces excitatory postsynaptic potential amplitude and blocks long term potentiation in hippocampal slices. Its close homology with cadherins, its rapid inducibility by neural activity, and its involvement in synaptic transmission suggest that Arcadlin may play an important role in activity-induced synaptic reorganization underlying long term memory.

  View details for Web of Science ID 000081196300087

  View details for PubMedID 10383464

• Cyclooxygenases and the central nervous system PROSTAGLANDINS & OTHER LIPID MEDIATORS Kaufmann, W. E., Andreasson, K. L., Isakson, P. C., Worley, P. F. 1997; 54 (3): 601-624

  Abstract

  Prostaglandins (PGs) were first described in the brain by Samuelsson over 30 years ago (Samuelsson, 1964). Since then a large number of studies have shown that PGs are formed in regions of the brain and spinal cord in response to a variety of stimuli. The recent identification of two forms of cyclooxygenase (COX; Kujubu et al., 1991; Xie et al., 1991; Smith and DeWitt, 1996), both of which are expressed in the brain, along with superior tools for mapping COX distribution, has spurred a resurgence of interest in the role of PGs in the central nervous system (CNS). In this review we will describe new data in this area, focusing on the distribution and potential role of the COX isoforms in brain function and disease.

  View details for Web of Science ID A1997YG18500001

  View details for PubMedID 9373877

• A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled JOURNAL OF BIOLOGICAL CHEMISTRY Wang, Y. S., Macke, J. P., Abella, B. S., Andreasson, K., Worley, P., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. 1996; 271 (8): 4468-4476

  Abstract

  In Drosophila melanogaster, the frizzled gene plays an essential role in the development of tissue polarity as assessed by the orientation of cuticular structures. Through a combination of random cDNA sequencing, degenerate polymerase chain reaction amplification, and low stringency hybridization we have identified six novel frizzled homologues from mammals, at least 11 from zebrafish, several from chicken and sea urchin, and one from Caenorhabditis elegans. The complete deduced amino acid sequences of the mammalian and nematode homologues share with the Drosophila frizzled protein a conserved amino-terminal cysteine-rich domain and seven putative transmembrane segments. Each of the mammalian homologues is expressed in a distinctive set of tissues in the adult, and at least three are expressed during embryogenesis. As hypothesized for the Drosophila frizzled protein, the frizzled homologues are likely to act as transmembrane receptors for as yet unidentified ligands. These observations predict the existence of a family of signal transduction pathways that are homologous to the pathway that determines tissue polarity in Drosophila.

  View details for Web of Science ID A1996TW96000078

  View details for PubMedID 8626800

• INDUCTION OF BETA-A ACTIVIN EXPRESSION BY SYNAPTIC ACTIVITY AND DURING NEOCORTICAL DEVELOPMENT NEUROSCIENCE Andreasson, K., Worley, P. F. 1995; 69 (3): 781-796

  Abstract

  beta-A activin is a member of the transforming growth factor-beta family and has been implicated in nerve cell survival and inhibition of differentiation in vitro [Hashimoto M. et al. (1990) Biochem. biophys. Res. Commun. 173, 193-200; Schubert D. et al. (1990) Nature 344, 868-870]. In our studies to identify genomic mechanisms involved in long-term neuronal responses to synaptic activity, we have determined that beta-A activin messenger RNA is rapidly and transiently induced in neurons of the adult rat brain by excitatory synaptic input. Synaptic mechanisms involved in beta-A activin messenger RNA induction were examined in adult hippocampus and cortex using the long-term potentiation paradigm. beta-A activin messenger RNA is induced in granule cell neurons of the hippocampus by high-frequency synaptic stimuli that produce long-term potentiation, and this induction is blocked by the N-methyl-D-aspartate type glutamate receptor antagonist, dizocilpine. beta-A activin messenger RNA is expressed at basal levels in neurons of layers II/III and V/VI, and this expression rapidly decreases following sensory deafferentation of the visual cortex or systemic administration of dizocilpine, suggesting that beta-A activin expression is regulated by physiological excitatory synaptic activity. In developing brain, beta-A activin is expressed in the neocortex and neostriatum beginning at embryonic day 17. beta-A activin expression in late fetal cortex is enriched in postmitotic neurons at the lower boundary of the dense cortical plate. As development progresses, beta-A activin expression continues to be enriched in neurons at the boundary between the hypercellular cortical plate and the subjacent, more mature deep layers. This inside-out progression of beta-A activin expression follows the well-characterized radial gradient of cortical development. Expression of beta-A activin messenger RNA is rapidly regulated in early postnatal cortex and striatum by GABA and glutamate antagonists, suggesting that beta-A activin is also regulated as a rapid response gene in developing brain, and that the high basal levels reflect a steady-state response to developmental signals. Since activin receptors are enriched in neurons of developing and adult brain [Cameron V. A. et al. (1994) Endocrinology 134, 799-808; Roberts V. J. and Barth S. L. (1994) Endocrinology 134, 914-922], our observations suggest a role for activin signaling in neuronal responses to synaptic and developmental activity. In this study, we analyse the induction of expression of beta-A activin, a member of the transforming growth factor-beta family of secreted peptides, in response to synaptic activity and in the developing brain. The elevated and specific expression of beta-A activin during fetal and early postnatal neocortical development and its later regulation by excitatory activity postnatally and in the adult suggests that the activin signaling pathway functions at multiple developmental stages in the neuroplastic response.

  View details for Web of Science ID A1995TE43100010

  View details for PubMedID 8596648

• LTP SATURATION AND SPATIAL-LEARNING DISRUPTION - EFFECTS OF TASK VARIABLES AND SATURATION LEVELS JOURNAL OF NEUROSCIENCE Barnes, C. A., Jung, M. W., McNaughton, B. L., Korol, D. L., Andreasson, K., Worley, P. F. 1994; 14 (10): 5793-5806

  Abstract

  The prediction that "saturation" of LTP/LTE at hippocampal synapses should impair spatial learning was reinvestigated in the light of a more specific consideration of the theory of Hebbian associative networks, which predicts a nonlinear relationship between LTP "saturation" and memory impairment. This nonlinearity may explain the variable results of studies that have addressed the effects of LTP "saturation" on behavior. The extent of LTP "saturation" in fascia dentata produced by the standard chronic LTP stimulation protocol was assessed both electrophysiologically and through the use of an anatomical marker (activation of the immediate-early gene zif268). Both methods point to the conclusion that the standard protocols used to induce LTP do not "saturate" the process at any dorsoventral level, and leave the ventral half of the hippocampus virtually unaffected. LTP-inducing, bilateral perforant path stimulation led to a significant deficit in the reversal of a well-learned spatial response on the Barnes circular platform task as reported previously, yet in the same animals produced no deficit in learning the Morris water task (for which previous results have been conflicting). The behavioral deficit was not a consequence of any after-discharge in the hippocampal EEG. In contrast, administration of maximal electroconvulsive shock led to robust zif268 activation throughout the hippocampus, enhancement of synaptic responses, occlusion of LTP produced by discrete high-frequency stimulation, and spatial learning deficits in the water task. These data provide further support for the involvement of LTP-like synaptic enhancement in spatial learning.

  View details for Web of Science ID A1994PL02800006

  View details for PubMedID 7931545

• Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. Learning & memory Yamagata, K., Kaufmann, W. E., Lanahan, A., Papapavlou, M., Barnes, C. A., Andreasson, K. I., Worley, P. F. 1994; 1 (2): 140-152

  Abstract

  Programs of gene activation may underlie long-term adaptive cellular responses to extracellular ligands. We have used a differential cDNA cloning strategy to identify genes that are strongly induced by excitatory stimuli in the adult rat hippocampus. Here, we report the rat cDNA sequence of a zinc-finger transcription factor, Egr3/Pilot, and characterize its regulated mRNA expression in brain. Egr3 mRNA is rapidly and transiently induced in neurons of the hippocampus and cortex by electroconvulsive seizure. mRNA levels peak 2 hr after the seizure and remain elevated for as long as 8 hr. Egr3 mRNA is also rapidly induced in granule cells of the dentate gyrus by synaptic NMDA receptor activation elicited by patterned stimulation of the perforant pathway and by drugs that alter dopamine neurotransmission in the striatum. Basal levels of Egr3 mRNA in the cortex appear to be driven by natural synaptic activity because monocular deprivation rapidly decreases Egr3 mRNA in the deafferented visual cortex. Aspects of the protein structure, sequence-specific DNA binding, transcriptional activity, and regulation of Egr3 are highly similar to another zinc-finger transcription factor, Egr1/zif268. Moreover, we demonstrate colocalization of Egr3 and zif268 mRNAs in neurons of normal and stimulated cortex. Our studies suggest that interactions between these coregulated transcription factors may be important in defining long-term, neuroplastic responses.

  View details for PubMedID 10467592

• RAPID RESPONSE GENES AS MARKERS OF CELLULAR SIGNALING DURING CORTICAL HISTOGENESIS - THEIR POTENTIAL IN UNDERSTANDING MENTAL-RETARDATION INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE Kaufmann, W. E., Yamagata, K., Andreasson, K. I., Worley, P. F. 1994; 12 (4): 263-271

  Abstract

  Aberrations of dendritic morphology are seen in most forms of mental retardation (MR). Normal cortical development is dependent on neural activity that modulates developmental processes such as dendritic differentiation. Indeed, many of the classical histological correlates of MR are reproduced in models that alter activity during development. To explore the hypothesis that MR results from aberrant activity signals during development, it would be useful to have histochemical markers that are sensitive to neural activity. Recent studies indicate that certain immediate early genes (IEGs) are normally expressed at relatively high levels in cortical neurons during postnatal development and are rapidly regulated by natural activity. We have begun to assess the possible use of IEG markers to study MR by examining the pre- and postnatal developmental time course of a panel of known IEG transcription factors as well as a set of novel IEGs identified in our laboratory. One of these recently characterized clones encodes a novel, mitogen-inducible cyclo-oxygenase that is expressed during a critical period for dendritic formation and is regulated by N-methyl-D-aspartate-dependent synaptic activity and by environmental stimuli. These data suggest a role for prostaglandin signaling in postnatal cortical development. Other partially characterized novel IEGs are expressed in a cell-specific fashion in the cortical plate. Application of these histochemical markers to the study of MR pathogenesis in animal models is discussed.

  View details for Web of Science ID A1994PC30000005

  View details for PubMedID 7976483

• EXPRESSION OF A MITOGEN-INDUCIBLE CYCLOOXYGENASE IN BRAIN NEURONS - REGULATION BY SYNAPTIC ACTIVITY AND GLUCOCORTICOIDS NEURON Yamagata, K., Andreasson, K. I., Kaufmann, W. E., Barnes, C. A., Worley, P. F. 1993; 11 (2): 371-386

  Abstract

  Prostaglandins play important and diverse roles in the CNS. The first step in prostaglandin synthesis involves enzymatic oxidation of arachidonic acid, which is catalyzed by prostaglandin H(PGH) synthase, also referred to as cyclooxygenase. We have cloned an inducible form of this enzyme from rat brain that is nearly identical to a murine, mitogen-inducible cyclooxygenase identified from fibroblasts. Our studies indicate that this gene, here termed COX-2, is expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus. Neuronal expression is rapidly and transiently induced by seizures or NMDA-dependent synaptic activity. No expression is detected in glia or vascular endothelial cells. Basal expression of COX-2 appears to be regulated by natural synaptic activity in the developing and adult brain. Both basal and induced expression of COX-2 are inhibited by glucocorticoids, consistent with COX-2 regulation in peripheral tissues. Our studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain. The marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.

  View details for Web of Science ID A1993LU06500016

  View details for PubMedID 8352945