Katrin Andreasson

All Publications

• Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging. Science (New York, N.Y.) Tan, Y. J., Conley, T. E., Yao, F., García-Marqués, F. J., Akinyemi, D. E., Dinh, V. V., Wang, Q., Bermudez, A., Kim, J., Belk, J. A., Soehnlein, O., Pitteri, S. J., Andreasson, K. I. 2026; 393 (6808): eaea3075

  Abstract

  Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.

  View details for DOI 10.1126/science.aea3075

  View details for PubMedID 42462036

• A new blueprint of brain border immunity. Nature immunology Ennerfelt, H. E., Andreasson, K. I. 2026

  View details for DOI 10.1038/s41590-025-02404-3

  View details for PubMedID 41593241

  View details for PubMedCentralID 10336149

• 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

• 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

• Unveiling the age related metabolic shift of innate immune cells in response to stroke injury Iweka, C., Cabrera, M., Blacher, E., Alexandrova, L., Mcreynolds, M., Andreasson, K. AMER SOC CELL BIOLOGY. 2024

  View details for Web of Science ID 001462295700091

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. NPJ Parkinson's disease Wilson, E. N., Umans, J., Swarovski, M. S., Minhas, P. S., Mendiola, J. H., Midttun, Ø., Ulvik, A., Shahid-Besanti, M., Linortner, P., Mhatre, S. D., Wang, Q., Channappa, D., Corso, N. K., Tian, L., Fredericks, C. A., Kerchner, G. A., Plowey, E. D., Cholerton, B., Ueland, P. M., Zabetian, C. P., Gray, N. E., Quinn, J. F., Montine, T. J., Sha, S. J., Longo, F. M., Wolk, D. A., Chen-Plotkin, A., Henderson, V. W., Wyss-Coray, T., Wagner, A. D., Mormino, E. C., Aghaeepour, N., Poston, K. L., Andreasson, K. I. 2025; 11 (1): 96

  Abstract

  Recent studies demonstrate that Parkinson's disease (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). Here, we used mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. We found 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, CSF soluble TREM2 (sTREM2) and severity of both motor and non-motor PD clinical symptoms. Finally, PD patient subgroups with distinct KP profiles displayed distinct PD clinical features. These data validate the KP 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 10.1038/s41531-025-00964-7

  View details for PubMedID 40287426

  View details for PubMedCentralID PMC12033312