Blocking microglial reactivity via purinergic receptors prevents long-term cognitive deficits after transient ischemic attacks
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272954 | GEO | 2026/04/22
REPOSITORIES: GEO
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Project description:Our research presents a new animal model of transient ischemic attack (TIA) that mimics brief episodes without cell loss, but results in neuronal and behavioral deficits. We identified excessive microglial reactivity, driven by acute ATP release, as a key factor in post-TIA neurological deficits, which were ameliorated by inhibiting the P2Y12 receptor, a microglia-specific purinergic receptor in the brain parenchyma responsible for activity-dependent microglial cell-cell interactions. This finding suggests that modulation of microglial reactivity offers a promising strategy to prevent cognitive impairment in TIA patients, opening avenues for future research in this underexplored area.
2026-04-24 | PXD070754 | Pride
Project description:Blocking microglial reactivity via purinergic receptors prevents long-term cognitive deficits after transient ischemic attacks
| PRJNA1139706 | ENA
Project description:To explore the diverse platelet microRNA (miRNA) expression between high platelet reactivity (HPR) and low platelet reactivity (LPR) patients with acute coronary syndromes (ACS), we enrolled a cohort of ACS patients and performed miRNA expression profiling of platelets from four HPR and four LPR patients using human miRNA microarray system. VerifyNow P2Y12 assay was applied to indentify HPR and LPR. Venous blood was drawn from the patients and was centrifuged to prepare platelets. Among the candidate differentially expressed miRNAs, miR-15b expression was further confirmed to be lower in platelets of 22 HPR patients than 17 LPR by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). We enrolled a consecutive cohort of 290 ACS patients and assessed the platelet reactivity using VerifyNow P2Y12 assay. In this study, HPR was defined as M-bM-^IM-%300 platelet reactivity unit (PRU) while LPR <170 PRU. miRNA microarray analysis was performed in platelets of four HPR and four LPR patients with ACS.
2014-07-17 | E-GEOD-59488 | biostudies-arrayexpress
Project description:To explore the diverse platelet microRNA (miRNA) expression between high platelet reactivity (HPR) and low platelet reactivity (LPR) patients with acute coronary syndromes (ACS), we enrolled a cohort of ACS patients and performed miRNA expression profiling of platelets from four HPR and four LPR patients using human miRNA microarray system. VerifyNow P2Y12 assay was applied to indentify HPR and LPR. Venous blood was drawn from the patients and was centrifuged to prepare platelets. Among the candidate differentially expressed miRNAs, miR-15b expression was further confirmed to be lower in platelets of 22 HPR patients than 17 LPR by quantitative reverse-transcription polymerase chain reaction (RT-qPCR).
2014-07-17 | GSE59488 | GEO
Project description:The biological significance of microglia are highlighted by their critical role as the resident immune cells of the central nervous system. In this capacity, microglia maintain homeostasis through various pathways that include cell migration, phagocytosis as well as secretion of immune-related and signaling factors into the extracellular environment. Microglial reactivity is associated with a variety of functional outcomes that are highly context-dependent and therefore microglia can exhibit a wide range of phenotypes. Epigenetic regulation through DNA methylation and histone modifications has recently been implicated in this complex control of microglial reactivity. Specifically, in relation to histone methylation status, the histone demethylase KDM5B has been implicated in many pathophysiological states including alcohol use disorder (AUD), cancer, and inflammatory disorders; however, the cell type-specific role of KDM5B in microglial reactivity has yet to be fully investigated. In this study, transcriptomic and proteomic analyses were used to characterize the effects of KDM5B knockdown on microglial pathways using CRISPR editing of adult-derived murine microglial cells to generate a Kdm5b knockout pool. From this multi-omic analysis, over 34,000 genes and 9,000 proteins were identified across all replicates of wild-type (WT) and KDM5B-depleted microglia. Additionally, various stimuli including LPS, IL4, and alcohol were used to study the effects of KDM5B knockdown on immune reactivity in microglia using deep proteomic analysis. Through this deep characterization, an overall decrease in inflammatory and immune reactivity pathways was observed in KDM5B-depleted microglia, which was then functionally validated through measurement of secreted factors including TNFα, IL6, IL4, IL10, IL16, and SPP1. The results from this study has provided critical insight into KDM5B-mediated effects on microglial function as well as a molecular framework for future studies aimed to understand epigenetic regulation of microglia and implications in neurodegenerative disease pathogenesis and progression.
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Project description:Microglia maintain brain homeostasis through coordinated pathways, including cell migration, phagocytosis, and secretion of immune-related signaling factors. Microglial reactivity is associated with a variety of functional outcomes that are highly context-dependent with epigenetic regulation through DNA methylation and histone modificationsimplicated in this complex control of microglial plasticity. Specifically, in relation to histone methylation, lysine-specific demethylase 5B (KDM5B) has been associated with several pathophysiological states, including neurodevelopmental and inflammatory disorders, cancer, and alcohol use disorder; however, the cell-type-specific role of KDM5B in microglial reactivity has not been investigated. In this study, transcriptomic and proteomic analyses were used to characterize the effects of KDM5B depletion on microglial pathways in clustered regularly interspaced short palindromic repeats (CRISPR)-edited adult-derived murine microglial cells. Additionally, various immunomodulatory stimuli, including lipopolysaccharide, interleukin-4, and alcohol, were used to study the effects of KDM5B depletion on immune reactivity in microglia using deep proteomics and bioinformatic analysis. Through this comprehensive characterization, KDM5B-depleted microglia exhibited broad remodeling of immune reactivity, including reduced intracellular and secreted inflammatory responses to lipopolysaccharide as well as distinct modulation of alcohol- and interleukin-4-induced pathways, that was functionally demonstrated by altered cytokine secretion profiles. Results from this study provide critical insight into KDM5B-mediated immunological effects on microglial function.
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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli. We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/J mice aged 8- to 10-weeks old. One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased mass spectrometry and deep proteomic analysis to determine the molecular pathways related to microglial reactivity. Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early life alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis. This study provides novel insights into the long-term effects of early alcohol exposure on microglial function and the complexity of context-dependent microglial involvement in tau pathology. Consideration of early life environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.
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Project description:Analysis of more than 700 genes using the Neuroinflammation panel (NS_Mm_NeuroInflam_v1.0) of Nanostring technologies from isolated microglial cells in naive and TIA animals revealed that they have an activated phenotype even 3d after TIA.
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Project description:Physical exercise (PE) may be the single most important and accessible lifestyle habit throughout life, it inhibits the neuroinflammatory response and protects the brain against damage. As the innate cells in brain, microglia undergo morphological and functional changes to communicate with neurons protecting other neurons from injury. Herein, aiming at exploring the effect of PE on the communication microglia - neuron during acute ischemic cerebral infarction, we carried out running wheel training before the conduction of transient middle cerebral artery occlusion (tMCAO) in Cx3cr1-GFP mice. We found that microglial P2Y12 expression in the peri-infarct area was decreased, microglial dynamics and microglia - neuron communications were impaired, using in vivo two-photon imaging. PE upregulated microglial P2Y12 expression, increased microglial dynamics, and promoted the contact of microglia with neurons. As a result, PE inhibited neuronal Ca2+ overloads and protected against damage of the neuronal mitochondria in acute tMCAO. Mechanistically, PE increased the cannabinoid receptor 2 (CB2R) in microglia, promoted the phosphorylation of Nrf2 (NF-E2-related factor 2) at ser-344, increased the transcription factor level of Mafk, and up-regulated the level of P2Y12, whereby PE increased the levels of CB2R to promote microglia-neuron contacts to monitor and protect neuronal functioning.
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Project description:Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
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