Journal of Neuroinflammation最新文献

{"title":"Modular inflammation network discovery from large-scale phenotypic screening in genetically heterogeneous mouse brains.","authors":"Monica Xiong, Lisa A Miosge, Carolina Correa-Ospina, Claudia M Y Yan, Tiffany Cripps, Stefan Bauernfried, Yuanyuan Wang, Maggie Crow, Lucy X Morris, T Daniel Andrews, Andrew Trujillo, Mitchell G Rezzonico, Yuxin Liang, Qixin Bei, Zora Modrusan, Kimberly L Stark, Tracy J Yuen, Brad A Friedman, Jesse E Hanson, Edward M Bertram, Christopher J Bohlen","doi":"10.1186/s12974-025-03556-7","DOIUrl":"10.1186/s12974-025-03556-7","url":null,"abstract":"<p><p>The central nervous system (CNS) represents a uniquely immune-privileged environment, with inflammatory responses involving several resident CNS-specific cell types. While stereotyped cellular and transcriptional responses recur across varied diseases, relevant signaling pathways and regulatory networks are not fully understood. Here, we investigate multi-modal inflammatory gene networks at large scale by developing a high-throughput RNA-seq screening and analysis workflow. As proof-of-concept, we investigate genetically heterogeneous mice from a large-scale chemical mutagenesis screen to identify novel functionally relevant variants in six genes previously linked to human CNS disorders: Nrros, Ctsd, Smpd1, Idua, Nlrp1a, and Inpp5d. We leverage the readily interpretable data from our large-scale study to demarcate distinct inflammatory states arising from each mutation. In all, our work provides a validated analysis framework for identifying discrete gene expression modules that are engaged divergently across disease contexts, which can be used to discover novel regulators of CNS neuroimmune homeostasis.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"218"},"PeriodicalIF":10.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholecystokinin ameliorates cognitive impairment via inhibiting microglia phagocytosis of excitatory synapses in sepsis-associated encephalopathy mice.","authors":"Lei Chen, Zhen Li, Yubo Gao, Guangxi Piao, Yitong Li, Jingshu Hong, Qian Wang, Kaixi Liu, Jie Wang, Ailian Du, Luhua Chen, Xiangyang Guo, Zhengqian Li, Taotao Liu","doi":"10.1186/s12974-025-03554-9","DOIUrl":"10.1186/s12974-025-03554-9","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-associated encephalopathy (SAE) is characterised by cognitive impairment and is a common complication in patients with sepsis. Microglia are involved in various cognitive impairment-related diseases through phagocytic synapses. Cholecystokinin (CCK), an abundant neuropeptide in the brain, is closely related to cognitive function. However, the role of CCK in SAE and the relationship between CCK and microglial phagocytosis of synapses are unknown.</p><p><strong>Methods: </strong>Lipopolysaccharide (LPS) was used to construct SAE models in 3-month-old male mice and BV2 microglial cells. To investigate the effects of CCK on cognitive impairment in SAE model mice, we used exogenous CCK injection into the dorsal hippocampal CA1 region or the chemogenetic activation of CCK-positive neurons to promote endogenous CCK release. Morris water maze and fear conditioning test were used to assess cognitive function in mice. RNA sequencing was performed to explore the potential signalling pathways involved in CCK-induced neuroprotection. Western blot and immunofluorescence were used to assess the effects of CCK on microglial phagocytosis of synapses, neurotoxic astrocytes, and excitatory synapses. Whole-cell recording was used to determine excitatory synaptic transmission.</p><p><strong>Results: </strong>LPS successfully established in vivo and in vitro models of SAE. Both exogenous CCK injection and activation of CCK-positive neurons in hippocampal CA1 region attenuated cognitive impairment in SAE mice. Mechanistically, CCK significantly alleviated excitatory synaptic plasticity damage via inhibiting complement 1q (C1q)-mediated microglial phagocytosis of synapses and neurotoxic astrocyte polarisation. Moreover, in vitro SAE model of BV2 cells demonstrated that CCK exerts neuroprotective effects through microglial CCK2-type receptor.</p><p><strong>Conclusions: </strong>CCK may alleviate cognitive impairment by inhibiting microglia C1q-mediated phagocytosis of excitatory synapses, suggesting that both CCK drugs and specific activation of CCK-positive neurons are potential treatments for SAE.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"217"},"PeriodicalIF":10.1,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of cellular metabolism within the gut-brain axis is associated with behavioural changes in chronic intestinal inflammation.","authors":"Jeannie Devereaux, Ainsley M Robinson, Rhian Stavely, Majid Davidson, Rhiannon T Filippone, Ramya Ephraim, Dimitros Kiatos, Vasso Apostolopoulos, Kulmira Nurgali","doi":"10.1186/s12974-025-03536-x","DOIUrl":"10.1186/s12974-025-03536-x","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory bowel disease (IBD) is a chronic debilitating condition significantly affecting patient quality of life. Although the exact aetiology remains unknown, accumulating evidence has shown that disruption of the gut-brain axis may be related to the occurrence and development of chronic intestinal inflammation. Psychological disorders are highly prevalent in patients with IBD. However, an association between altered behaviour and dysregulated metabolic pathways within the gut-brain axis is yet to be explored.</p><p><strong>Methods: </strong>Metabolic multiplexed phenotyping system involving indirect calorimetry and flow-through respirometry monitors was used to assess energy metabolism in Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Depressive and anxiety-like behaviours were evaluated with light dark, open field, grooming, elevated plus maze, and forced swimming tests. To investigate underlying mechanisms of the metabolic changes in Winnie mice, glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation gene expressions were determined by transcriptome analysis using high-throughput sequencing of mRNA extracted from the distal colon and brain samples.</p><p><strong>Results: </strong>Our findings showed that energy metabolism and spontaneous activity were reduced in Winnie mice corresponding to alterations in the expression of cellular metabolism-associated genes in the distal colon. Winnie mice displayed depressive and anxiety-like behaviours reflecting downregulation of glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation in the distal colon and brain. Subsequent analyses showed pro-inflammatory cytokine expression was upregulated in the Winnie mouse brain.</p><p><strong>Conclusions: </strong>These data provide evidence that the dysregulation of cellular metabolism within the gut-brain axis underlies changes in behaviour and energy metabolism in chronic intestinal inflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"216"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eosinophil recruitment and activation in the central nervous system of patients with subarachnoid neurocysticercosis.","authors":"Emily Miltenberger, Janitzio Guzmán, Rodaba Rahim, Miranda Yu, Michelle Makiya, Perla Adames Castillo, Soo Ching Lee, Theodore E Nash, Amy D Klion, Thomas B Nutman, Elise M O'Connell","doi":"10.1186/s12974-025-03540-1","DOIUrl":"10.1186/s12974-025-03540-1","url":null,"abstract":"<p><strong>Background and objectives: </strong>Subarachnoid neurocysticercosis (SANCC) is the most severe manifestation of neurocysticercosis. Most complications (communicating hydrocephalus, ischemic stroke, aneurysm, and subarachnoid hemorrhage) are due to inflammation localized to the central nervous system (CNS). The role of eosinophils in the inflammation associated with SANCC has not been previously studied.</p><p><strong>Methods: </strong>Cryopreserved CSF collected as part of a clinical trial for neurocysticercosis (NCC) were assessed for analytes associated with eosinophil activation and recruitment using multiplex bead assays in both subjects with SANCC (n = 28) and in NCC-negative controls (n = 26). The SANCC patients underwent chart review for extraction of clinical variables as well as grouping by disease severity to identify analytes that may be associated with the development of more severe symptoms of SANCC.</p><p><strong>Results: </strong>Eosinophil granule proteins (EGPs - ECP, EDN, and EPO), markers of eosinophil activation, were elevated in the CSF of SANCC patients compared to controls. Moreover, the eosinophil-associated cytokines/chemokines IL-5, IL-13, IL-18, CCL24/eotaxin-2, and CCL26/eotaxin-3 were also significantly elevated in the CSF of SANCC patients compared to controls. In those for whom there were paired specimens (n = 13) from baseline and following cure, there was a significant reduction in these cytokines/chemokines (except CCL26/eotaxin-3). The percentage of CSF white blood cells that were eosinophils was positively correlated with EDN, EPO, IL-5, IL-13, CCL24, CCL26, CCL8, CCL13, and CCL5/RANTES, as well as the time it took to achieve biomarker cure. When SANCC patients were subdivided between those with severe disease and those with non-severe disease, the levels of eosinophil cationic protein (ECP), the CCR3 ligands (CCL7 and CCL5), CCL4, IL-18, and IL-1RA discriminated clearly between these 2 groups.  DISCUSSION: These data provide evidence for eosinophil recruitment and activation in the subarachnoid space in patients with SANCC, as well as for a potential role of eosinophils in driving inflammation-associated complications.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"215"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncBADR promotes T cell-mediated autoimmunity by binding Mccc1 and Pcca to regulate BCAAs degradation.","authors":"Yanting Lei, Jing Yu, Xinrui Huo, Zhaoying Li, Jing Wang, Yixiang Jiang, Ying Yu, Yan Huang, Wenkang Jiang, Jiangtian Tian, Dan Kong, Yumei Liu, Xijun Liu, Xiujuan Lang, Hulun Li, Bo Sun","doi":"10.1186/s12974-025-03538-9","DOIUrl":"10.1186/s12974-025-03538-9","url":null,"abstract":"<p><p>T cell dysfunction is a pivotal driving factor in autoimmune diseases, yet its underlying regulatory mechanisms remain incompletely understood. The role of long non-coding RNAs (lncRNAs) in immune regulation has gradually been recognized, although their functional mechanisms in T cells remain elusive. This study focuses on lncBADR (LncRNA Branched-chain Amino acids Degradation Regulator), elucidating its mechanism by which it regulates branched-chain amino acids (BCAAs) metabolism to influence T cell effector functions. Mice with specific knockout of lncBADR (T cell^lncBADR-/-) exhibited markedly ameliorated experimental autoimmune encephalomyelitis (EAE) symptoms. Mechanistic investigations revealed that lncBADR inhibits BCAAs degradation by binding to the enzymes Mccc1 and Pcca, leading to the accumulation of BCAAs within T-cells. This, in turn, activates the mTOR-Stat1 signaling pathway, promoting IFN-γ secretion and exacerbating EAE pathology. In contrast, knockout of lncBADR restored BCAAs degradation, significantly reducing IFN-γ secretion in T cells and suppressing their pathogenic functions. Further studies demonstrated that high-BCAAs feeding partially reversed the protective effects of lncBADR knockout, indicating that lncBADR plays a crucial role in autoimmune inflammation by regulating BCAAs metabolism. This study offers new insights into targeting lncBADR or modulating BCAAs metabolism as potential therapeutic strategies for autoimmune diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"213"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner.","authors":"Jiahui Liu, Ali Zaidi, Christian J Pike","doi":"10.1186/s12974-025-03534-z","DOIUrl":"10.1186/s12974-025-03534-z","url":null,"abstract":"<p><p>Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglia/macrophage TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglia/macrophage TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"214"},"PeriodicalIF":10.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage expression of P2X7 controls autoimmune uveitis.","authors":"Paul-Alexandre Déchelle-Marquet, Yueshen Che, Camille Roux, Frédéric Blond, Kaitryn E Ronning, Sébastien Augustin, Pauline Lagouge-Roussey, Caroline Nous, Sara Touhami, Bahram Bodaghi, Jean Kanellopoulos, Sahil Adriouch, Xavier Guillonneau, Florian Sennlaub, Cécile Delarasse","doi":"10.1186/s12974-025-03529-w","DOIUrl":"10.1186/s12974-025-03529-w","url":null,"abstract":"<p><p>The release of danger-associated molecular patterns (DAMPs) such as ATP from stressed or damaged cells is a key initiator of sterile inflammation. In autoimmune diseases, extracellular ATP acts as a potent pro-inflammatory signal by activating the purinergic receptor P2X7, which is expressed on both mononuclear phagocytes (MPs) and T cells-key drivers of pathological processes. While it is well established that P2X7 mediates ATP-dependent immune activation, its cell-specific contributions to innate versus adaptive immunity in autoimmune conditions remain unclear, especially in autoimmune uveitis. Here we used the experimental autoimmune uveoretinitis (EAU) mouse model to delineate the cellular mechanisms underlying P2X7's role in autoimmune responses. Using a combination of multiple cell-specific conditional models and transcriptomic approaches, we showed a pivotal role forP2X7 expressed by MPs in orchestrating T-cell mediated autoimmune responses. P2X7 deficiency in MPs decreased disease severity. Additionally, cell-specific transcriptomic analyses, including single-cell analyses, revealed that P2X7 exerted distinct modulatory effects across monocyte-derived macrophages (MdM) versus microglia. In MdM, lack of P2X7 was associated with reduced expression of genes related to the inflammasome, phagocytosis pathways, and components of the complement system, leading to a marked decrease in pathogenic Th17 cell frequency in the retina. In microglia, P2X7 deficiency instead particularly impacted an IFN-responsive microglial subset that is normally characteristic of EAU. By specifically deleting P2X7 in microglia, we demonstrate its role in driving pathogenic processes in this cell population. These findings suggest that inhibition of P2X7 could be a promising therapeutic strategy in autoimmune neuroinflammatory disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"212"},"PeriodicalIF":10.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12465806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Ephrin receptor signaling in the paraventricular nucleus attenuates psoriasis-like dermatitis via synaptic plasticity and immune homeostasis modulation.","authors":"Qingyu Ren, Zhanpeng Gao, Weikai Han, Yaqi Tang, Mengdong Shi, Yanan Yue, Xijia Xin, Chenyu Zhang, E Liu, Bo Dong, Qingwei Yue, Jinhao Sun","doi":"10.1186/s12974-025-03539-8","DOIUrl":"10.1186/s12974-025-03539-8","url":null,"abstract":"<p><p>Psoriasis pathophysiology involves dysregulated neuroimmune crosstalk, yet the central mechanisms involved remain incompletely understood. Here, we show that the hypothalamic paraventricular nucleus (PVN) orchestrates cutaneous inflammation via a transsynaptic brain-skin circuit. Using neural tracing and chemogenetic approaches, we revealed functional connectivity between the PVN and both sympathetic neurons and psoriatic skin. Reactivation of imiquimod (IMQ)-induced PVN-transgenic targeted recombination in active population (TRAP) neurons (which form a specific \"inflammatory memory\") is essential for psoriasis progression and can drive chronic inflammation. Single-nucleus RNA sequencing (snRNA-seq) identified ephrin receptor A7 (Epha7) as a critical mediator of synaptic plasticity in PVN inflammatory engram neurons. The inhibition of Ephrin receptor and ligand binding in the PVN normalized dendritic spine remodelling, suppressed sympathetic nerve hyperactivity, and restored the balance of Th17/Treg cells in psoriatic-like mice. Mechanistically, blockade of the Ephrin receptor attenuated sympathetic norepinephrine overflow, thereby mitigating Th17-driven inflammation. This study identifies a PVN-sympathetic-skin axis in which the inhibition of Epha7 in the PVN restores skin immune homeostasis. Furthermore, this study elucidates the central neural mechanisms of skin inflammation and promotes the transition of psoriasis treatment from single-target approaches to a synergistic neuroimmune strategy involving \"brain-skin\" interactions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"211"},"PeriodicalIF":10.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockout of P2Y12 receptor facilitates neuronal envelopment by reactive microglia and accelerates prion disease.","authors":"Natallia Makarava, Tarek Safadi, Olga Bocharova, Olga Mychko, Narayan P Pandit, Kara Molesworth, Ukpong B Eyo, Ilia V Baskakov","doi":"10.1186/s12974-025-03542-z","DOIUrl":"10.1186/s12974-025-03542-z","url":null,"abstract":"<p><strong>Background: </strong>Microglia continuously monitor neuronal health through somatic purinergic junctions, where microglial processes establish dynamic contacts with neuronal cell bodies. The P2Y12 receptor is a key component of these junctions, essential for intercellular communication between ramified microglia and neurons under homeostatic conditions. However, during chronic neurodegeneration, such as that seen in prion diseases, microglia transition from process-based surveillance to extensive body-to-body interactions, enveloping neuronal somata. Despite its widespread use as a homeostatic marker, the functional role of P2Y12 in chronic neurodegenerative contexts remains largely unexplored.</p><p><strong>Methods: </strong>We investigated how genetic deletion of P2Y12 affects microglial morphology and microglia-neuron interactions in both healthy and prion-infected adult mice. In parallel, we assessed the impact of P2Y12 loss on prion disease progression and associated neuropathology.</p><p><strong>Results: </strong>In healthy adult mice, deletion of P2Y12 significantly disrupted canonical process-to-soma contacts, while paradoxically promoting increased microglia-neuron body-to-body interactions. This finding uncovers a previously unrecognized, P2Y12-independent mode of microglial engagement with neurons. Strikingly, in prion-infected mice, P2Y12 loss significantly increased the prevalence of neuronal envelopment by reactive microglia, and accelerated disease progression. Notably, this acceleration occurred without affecting prion accumulation or hippocampal neuronal loss, implicating altered microglia-neuron interactions - specifically excessive envelopment - as a key driver of disease exacerbation.</p><p><strong>Conclusions: </strong>This study redefines P2Y12 not as a passive marker of homeostasis but as an active regulator of neuroimmune dynamics. We demonstrate that P2Y12 is essential for maintaining balanced microglia-neuron communication under physiological conditions and for restraining maladaptive microglial behavior during chronic neurodegeneration associated with prion disease. These findings uncover a novel mechanism by which microglia contribute to disease progression and position P2Y12 as a potential therapeutic target for modulating microglial responses in neurodegenerative disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"210"},"PeriodicalIF":10.1,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulatory extracellular vesicles transport complement C1q for promoting neuronal amyloid-β production in Alzheimer's disease.","authors":"Yang Yu, Wenjun Xiao, Zhixin Ma, Xiaomei Yi, Tianyu Zhong, Zhigang Li","doi":"10.1186/s12974-025-03528-x","DOIUrl":"https://doi.org/10.1186/s12974-025-03528-x","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"209"},"PeriodicalIF":10.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}