Journal of Neuroinflammation最新文献

{"title":"FGF13 alleviates astrocytic apoptosis via JIP2 inhibition in the hippocampus and mitigates depression-like behavior.","authors":"Rui Zheng, Yujie Zhang, Zheng Tu, Yawen Luo, Huixin Lin, Xuehai Chen, Zhiyang Huang, Luocheng Shao, Yanyan Zheng, Zhouguang Wang","doi":"10.1186/s12974-026-03960-7","DOIUrl":"10.1186/s12974-026-03960-7","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is one of the leading causes of disability worldwide and significantly increases the risk of premature death and other diseases. Astrocyte loss is a key pathological hallmark of MDD, yet the underlying mechanisms remain unclear. Here, we identify fibroblast growth factor 13 (FGF13) as a critical regulator of astrocyte apoptosis in depression, which is closely associated with depression-like behaviors in mice. In depressive models, FGF13 expression is markedly reduced, particularly in astrocytes, accompanied by astrocyte apoptosis in the hippocampal region and decreased synaptic protein levels in the nervous system. Astrocyte-specific knockout of FGF13 induces astrocytic apoptosis, exacerbates inflammatory levels, and aggravates depression-like behaviors in mice. In contrast, astrocyte-specific overexpression of FGF13 significantly attenuates both astrocyte apoptosis and inflammation, and effectively ameliorates depression-like behaviors. Mechanistically, FGF13 directly binds to JIP2 protein, inhibits its activity, and subsequently blocks the downstream JIP2-JNK signaling pathway, thereby suppressing Bax/Bcl-2-mediated astrocyte apoptosis. These findings reveal a key mechanism by which FGF13 regulates astrocyte death in depression and highlight its potential as a therapeutic target for MDD, offering new insights for the development of antidepressant drugs targeting astrocytes.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411970","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":"Neuroinflammatory suppression of astrocytic BMAL1 defines a selective reactive astrocyte program.","authors":"Xingqi Meng, Ming Ho Choi, Xuebing Zhang, Jin Young Kim","doi":"10.1186/s12974-026-03953-6","DOIUrl":"10.1186/s12974-026-03953-6","url":null,"abstract":"<p><p>Astrocyte reactivity is a hallmark of neuroinflammatory diseases. Astrocytes contain functional circadian clocks that drive daily homeostatic rhythms, making them potential regulators of the transition from homeostatic to reactive states. However, it remains unclear whether neuroinflammatory conditions alter endogenous astrocyte clocks and whether these clock alterations contribute to pathway changes associated with reactivity. Here, we combined in vivo and in vitro lipopolysaccharide (LPS)-based neuroinflammation models with circadian profiling, chromatin analysis, and bulk RNA-sequencing of purified microglia and astrocytes. In vivo and in vitro, neuroinflammation reduced the amplitude of Bmal1 and Per1 rhythms and changed clock gene expression patterns across circadian time, while reactive markers gained rhythmic expression. In vitro, these clock changes occurred in astrocytes exposed to the inflammatory glial environment, but not after direct LPS treatment, indicating that paracrine glial signaling is the main driver. RNA-sequencing of microglia from the same neuroinflammatory glial cultures identified Il1b and Tnf as strong candidate mediators, and combined IL-1β/TNFα treatment was sufficient to suppress astrocyte clock gene expression and induce reactive marker expression. This clock suppression was accompanied by a modest reduction in BMAL1 protein but a stronger reduction in average BMAL1 occupancy at multiple clock target loci, including Per1 and Nr1d1. To define BMAL1-dependent pathways in astrocytes, we compared gene expression in wild-type and Bmal1-deficient astrocytes, and then compared these changes with those observed under neuroinflammatory conditions. Bmal1 loss alone did not reproduce the full inflammatory response. Instead, it identified a selective subset of the reactive astrocyte transcriptome, mainly involving suppression of cell-cycle and chromosome-segregation pathways with limited innate immune activation. Together, these findings identify astrocytic BMAL1 as a regulator of a selective pathway subset within reactive astrocytes in response to neuroinflammatory conditions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412041","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":"Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis.","authors":"Karen M J van Loo, Daniel S Galvis-Montes, Annika Breuer, Juliane L Berns, Chiara A Hummel, Tobias Baumgartner, Moritz Freyberg, Katharina M Mair, Jan Bauer, Theodor Rüber, Ashley J van Waardenberg, Motaz Hamed, Valeri Borger, Hartmut Vatter, Rainer Surges, Susanne Schoch, Albert J Becker, Julika Pitsch","doi":"10.1186/s12974-026-03951-8","DOIUrl":"10.1186/s12974-026-03951-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters.</p><p><strong>Methods: </strong>We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort.</p><p><strong>Results: </strong>Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated.</p><p><strong>Conclusion: </strong>These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404906","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":"Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.","authors":"Pilar González-García, Ignacio Serrano-Martínez, Eliana Barriocanal-Casado, Alejandro Cuenca-Martagón, Pablo Vargas-Rodríguez, Norma Adán, Irene Forte-Lago, Juan Carlos Morales, Patricia Gomez-Suaga, Júlia Bonet-Freixinet, Silvia Ginés, Luis C López, Elena González-Rey","doi":"10.1186/s12974-026-03947-4","DOIUrl":"10.1186/s12974-026-03947-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Huntington's disease (HD) is an inherited, fatal neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene, leading to progressive motor, cognitive and psychiatric impairment. Despite its monogenic origin, HD pathogenesis is multifactorial, with convergent contributions from mitochondrial dysfunction, oxidative stress, synaptic failure, and chronic neuroinflammation, which drive neuronal vulnerability and degeneration, particularly within the striatum. Current clinical management remains exclusively symptomatic and fails to halt disease progression, highlighting a critical unmet need for strategies targeting fundamental pathogenic mechanisms. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory properties and has recently been implicated in the regulation of mitochondrial function. Notably, cortistatin deficiency is associated with exacerbated systemic and central inflammation, suggesting that impaired cortistatin signaling may contribute to neurodegeneration. However, its role in HD pathophysiology remains unexplored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We performed a comprehensive reanalysis of publicly available transcriptomic datasets from HD patients to assess cortistatin expression, followed by validation in experimental HD models. Wild-type and cortistatin-deficient mice treated with 3-nitropropionic acid served as pharmacological HD models, enabling evaluation of cortistatin-dependent disease severity. Behavioral assessments, glial and oxidative markers, and immune factors were evaluated to determine neurological dysfunction and inflammatory responses. Complementary in vitro studies were conducted in striatal neurons expressing mutant huntingtin to examine mitochondrial integrity, inflammatory signaling, metabolic function, and mitochondria-endoplasmic reticulum interactions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Cortistatin expression was significantly reduced in postmortem HD human brains and across experimental HD models. Cortistatin deficiency exacerbated motor deficits, neuropathological alterations, inflammatory activation, and neuronal vulnerability in HD context. At the cellular level, reduced cortistatin expression was accompanied by amplified inflammatory signaling, disrupted mitochondrial integrity, impaired mitochondria-endoplasmic reticulum interactions, and increased oxidative stress. Conversely, exogenous cortistatin administration attenuated inflammatory mediator production, preserved mitochondrial structure, and improved redox balance in mutant huntingtin-expressing striatal neurons.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings identify cortistatin deficiency as a previously unrecognized contributor to HD pathogenesis and establish cortistatin as a key modulator of neuroinflammation and mitochondrial homeostasis. These results support cortistatin-based strategies as a promising disease-modifying therapeutic avenue for HD ","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404935","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":"The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental support.","authors":"Serena Seminara, Aurora Bianchi, Davide Comolli, Marco Spreafico, Wenjie Liao, Hemanta Sarmah, Grazia Iannello, Barbara Corneo, Gianluigi Forloni, Elisa R Zanier, Massimiliano De Paola, Alessandro Fantin, Stefano Fumagalli","doi":"10.1186/s12974-026-03948-3","DOIUrl":"10.1186/s12974-026-03948-3","url":null,"abstract":"<p><p>Myeloid progenitor cells colonize the brain during embryogenesis and differentiate in microglia. Microglia shape neuronal wiring during development and maintain brain homeostasis in adulthood, both actions requiring intact cytoskeletal functionality. The Wiskott-Aldrich syndrome protein (WASp) mediates cytoskeletal dynamics of peripheral myeloid cells, suggesting a similar role in microglia. To investigate WASp's role in microglia, we impaired WASp function in human induced pluripotent stem cells-derived microglia (iMicro) and zebrafish embryos.WASp colocalized with the actin cytoskeleton at membrane ruffles in phagocytic iMicro and appeared required for their phagocytic function. When co-cultured with neuronal cells, the support of iMicro with defective WASp function to neuronal wiring was impaired. Similarly, zebrafish embryos exposed to WASp inhibition showed brain accumulation of uncleared apoptotic bodies, reduced brain colonization of myeloid cells, and impaired sensorimotor response to mechanical stimuli.These findings identify WASp as a regulator of microglial phagocytosis and cytoskeletal dynamics, with implication in neuronal wiring during neurodevelopment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396820","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":"Correction: SIRT2 Inhibition promotes microglia LC3-associated phagocytosis via NRF2/CD36 after the experimental subarachnoid hemorrhage.","authors":"Bin Sheng, Xiangxin Chen, Tao Tao, Jiaqing Sun, Wei Li, Lingyun Wu, Zheng Peng, Xiaojian Li, Zhengxu Zhou, Qian Yu, Yeping Ling, Prativa Sherchan, Jerry J Flores, Jiping Tang, Lei Huang, Chunhua Hang, John H Zhang","doi":"10.1186/s12974-026-03943-8","DOIUrl":"10.1186/s12974-026-03943-8","url":null,"abstract":"","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13340357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404888","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":"Dysregulated glia and periglomerular cells in the olfactory bulb and altered lipocalins in the olfactory epithelium underlie olfactory dysfunction in a murine model of eosinophilic chronic rhinosinusitis.","authors":"Ryoji Kagoya, Hironobu Nishijima, Kyohei Horikiri, Kei Ogawa, Megumi Kishimoto-Urata, Shinji Urata, Kenji Kondo","doi":"10.1186/s12974-026-03939-4","DOIUrl":"10.1186/s12974-026-03939-4","url":null,"abstract":"<p><strong>Background: </strong>Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease. It is characterized by type 2 inflammation and olfactory dysfunction. Although olfactory dysfunction in patients with ECRS may have sensorineural and central components, the underlying mechanism remains to be elucidated. We aimed to investigate changes in the olfactory bulb (OB) and olfactory epithelium (OE) associated with sinonasal type 2 inflammation, using a murine model of ECRS.</p><p><strong>Methods: </strong>We developed a murine model of ECRS based on the topical application of calcipotriol and ovalbumin for 14 days and subsequent daily intranasal challenge with ovalbumin for 5 days. Histopathological analyses were performed to assess glial cells and periglomerular cells (PGCs) in the OB. Bulk RNA sequencing was performed to determine the impact of sinonasal type 2 inflammation on the OB and OE. Differentially expressed genes were identified using a false discovery rate < 0.05 (Benjamini-Hochberg adjustment). For molecules exhibiting marked fluctuations at the gene expression level, the protein expression was evaluated using enzyme-linked immunosorbent assay (ELISA).</p><p><strong>Results: </strong>In the ECRS group, a significant increase was noted in the number of microglia/macrophages and astrocytes in the OB. In addition, the number of tyrosine hydroxylase-positive PGCs was significantly reduced in the OB of mice with ECRS. Bulk RNA sequencing analysis revealed a significant decrease in the gene expression levels of the lipocalin family in both the OB and OE. Subsequent ELISA confirmed a significant reduction in the protein levels of lipocalin 4 and major urinary protein 5 in the OE; conversely, lipocalin 3 levels in the OE were significantly increased. No significant differences were observed in the protein expression levels of these molecules within the OB.</p><p><strong>Conclusion: </strong>Sinonasal type 2 inflammation causes various changes in the olfactory system. These changes may be involved in the pathogenesis of sensorineural and central olfactory dysfunction in ECRS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387663","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":"Targeting the cGAS-STING pathway alleviates neuroinflammation and cognitive impairment induced by chronic infection of Toxoplasma gondii.","authors":"Yihui Xing, Huiling Lv, Peixuan He, Yongyao Xu, Weifan Shen, Ziyan Gu, Fan Zeng, Yifan Zhang, Kai Sui, Yurui Shi, Yinghua Yu, Wei Pan, Cheng He","doi":"10.1186/s12974-026-03937-6","DOIUrl":"10.1186/s12974-026-03937-6","url":null,"abstract":"<p><p>Chronic infection of Toxoplasma gondii has been established as a contributor to cognitive impairment via inducing sustained neuroinflammation and synaptic damage. However, the underlying mechanisms remain poorly understood. As a key regulator of both neuroinflammation and cellular senescence, Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is implicated in pathogenesis induced by T. gondii infection. Here, we found that cGAS-STING pathway was activated in the cerebral cortex of mouse chronically infected with T. gondii, as indicated by the elevated protein levels of cGAS and STING, and increased phosphorylation of TBK1 and IRF3. Pharmacological inhibition of this pathway with RU.521 and H151, specific inhibitors of cGAS and STING, significantly alleviated T. gondii-induced cognitive impairment and neuronal damage. Moreover, chronic T. gondii infection was shown to trigger senescence characterized by increased expression of senescence markers P16, P21 and P53, and senescence-associated secretory phenotypes (SASPs), including Il-1β, Il-6, Tnf-α, Cxcl1, Cxcl10 and Mmp9. In addition, elevated expression of β-galactosidase, a senescence marker, was predominantly observed in neurons compared to microglia and astrocytes, indicating a primary role for neurons in infection-associated senescence. Notably, these phenotypes of senescence were rescued by inhibition of the cGAS-STING pathway. Collectively, our findings demonstrate that chronic infection of T. gondii activates the cGAS-STING pathway, which in turn drives neuroinflammation and cognitive dysfunction in which neuronal senescence plays a contributory role. Targeting this pathway alleviates T. gondii-induced cognitive decline, highlighting its therapeutic potential against infection-triggered neurodegenerative diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387601","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":"Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.","authors":"Mahsa S Bavarsad, Felipe L Pereira, Marina M Reinhardt, Abhijit Satpati, Salvatore Spina, William W Seeley, William Jagust, Gil D Rabinovici, Ari Green, Lea T Grinberg","doi":"10.1186/s12974-026-03945-6","DOIUrl":"10.1186/s12974-026-03945-6","url":null,"abstract":"<p><strong>Background: </strong>Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely defined, limiting interpretation of emerging CSF1R-PET signals. We sought to build a cross-disease, multi-region, quantitative map of CSF1R-positive microglia in neurodegenerative conditions and progressive multiple sclerosis (MS) lesions, with an exploratory comparison to presynaptic marker burden.</p><p><strong>Methods: </strong>CSF1R mRNA‑positive microglia were quantified by RNAscope across six cortical regions (MFG, IFG, ITG, AG, CA1, EC) in early‑onset Alzheimer's disease (EOAD), late‑onset AD (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions due to progranulin mutation (FTLD‑GRN), and in primary and secondary progressive MS (PPMS, SPMS) within cortical gray‑matter plaques, plaque-adjacent gray matter and white matter. Positivity was defined a priori as ≥ 3 puncta with housekeeping‑probe pass and negative‑control verification, counting blinded, and densities were cortical‑thickness corrected. Iba-1 immunolabeling verified microglial identity. Western blot provided protein‑level verification. We explored ROI‑level associations of CSF1R with SV2A and synaptophysin previously measured in the same regions/cases.</p><p><strong>Results: </strong>In neurodegeneration, increases were smaller and region‑specific (e.g., EOAD-ITG/CA1; LOAD-AG; PSP-AG; FTLD‑GRN-IFG/ITG/AG/EC), with minimal white‑matter change. In progressive MS, gray-matter CSF1R-positive microglia densities did not differ from controls, whereas SPMS white matter was increased. Exploratory analysis showed that CSF1R and SV2A were positively associated across ROIs in neurodegenerative diseases (e.g., PSP approximately ρ = 0.66), and weakest in LOAD; synaptophysin showed similar patterns, suggesting that regions with higher CSF1R-positive microglia density can coincide with relative preservation of presynaptic markers.</p><p><strong>Conclusions: </strong>A cross‑disease, region‑resolved map reveals region‑specific changes in CSF1R + cell density in neurodegeneration, but only white matter in MS. These findings provide the histological context needed to interpret future CSF1R‑PET. Prospective studies pairing CSF1R‑PET with SV2A‑PET and multiplex tissue profiling are warranted to define microglial states and synaptic outcomes in vivo.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13602470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382188","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":"Human umbilical cord blood mononuclear cells ameliorate vascular dementia by modulating microglial myelin debris handling and white matter injury.","authors":"Xueyi Wen, Kejing He, Cheng Huang, Congying Shi, Wei Wei, Yusheng Zhang, Zhenguo Yang, Keshen Li","doi":"10.1186/s12974-026-03929-6","DOIUrl":"10.1186/s12974-026-03929-6","url":null,"abstract":"<p><p>Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382239","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}