Acta Neuropathologica Communications最新文献

{"title":"Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.","authors":"Kuo Liao, Jianing Lin, Yangfan Zhou, Sebastian A Lewandowski","doi":"10.1186/s40478-026-02449-x","DOIUrl":"10.1186/s40478-026-02449-x","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1^low perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered oligodendroglial cell development and increased myelination in SCN2A gain-of-function-linked epilepsy.","authors":"Constanza Bravo-Rossainz Baez, Xian Xin, Hang Lyu, Daniil Kirianov, Ying Sun, Erik Späte, Mariapia Grassia, Birgit Engeland, Malte Stockebrand, Konstantin Khodosevich, Ulrike B S Hedrich, Dirk Isbrandt, Friederike Pfeiffer","doi":"10.1186/s40478-026-02437-1","DOIUrl":"10.1186/s40478-026-02437-1","url":null,"abstract":"<p><p>Gain-of-function variants in SCN2A, encoding the voltage-gated sodium channel Na_V1.2, cause developmental and epileptic encephalopathies characterized by seizures, developmental delay, and white matter abnormalities. While Na_V1.2 is known to regulate neuronal excitability, its role in oligodendroglial cells is unclear. Here, we show that Na_V1.2 is expressed in early oligodendrocyte lineage stages. In mice carrying the gain-of-function Scn2a^p.A263V variant, oligodendrocyte precursor cells displayed similar Na_V1.2 expression, but altered electrophysiological properties and calcium signaling. Single-cell transcriptomics revealed stage-specific changes in oligodendroglial maturation during early postnatal development, associated with lower variability and slightly faster conduction velocities. In adult mutant mice, gray matter myelination was increased without changes in oligodendrocyte numbers or myelin structure. Since Na_V1.2 was absent from mature oligodendrocytes, the enhanced myelination likely reflects an activity-dependent adaptation to altered neuronal network activity rather than a primary myelinopathy. These findings identify a glial contribution to SCN2A-related disease mechanisms and underscore the need to consider neuron-glia interactions when developing targeted therapies for epilepsy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study.","authors":"Jie Pan, Jaume Fores-Martos, Claire Delpirou Nouh, Tanner D Jensen, Kristen Vallejo, Romain Cayrol, Saman Ahmadian, Euan A Ashley, Michael D Greicius, Inma Cobos","doi":"10.1186/s40478-026-02443-3","DOIUrl":"10.1186/s40478-026-02443-3","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiscale characterization and distribution of the thyroid hormone transporter MCT8 in the adult and aged human brain.","authors":"Jonas Rotter, Toni Kirmann, Jana Brendler, Larissa Anthofer, Nina Maria Wilpert, Stefan Hallermann, Heike Biebermann, Ingo Bechmann","doi":"10.1186/s40478-026-02435-3","DOIUrl":"https://doi.org/10.1186/s40478-026-02435-3","url":null,"abstract":"<p><p>The local availability of thyroid hormones (TH) depends on TH transporters such as monocarboxylate transporter 8 (MCT8, encoded by SLC16A2). Mutations of SLC16A2 cause Allan-Herndon-Dudley syndrome (AHDS), a disorder characterized by severe neurodevelopmental and motor deficits. While MCT8's importance in foetal brain development is well-established, its precise topographical, cellular, and subcellular distribution in the adult human brain has remained largely uncharacterized, limiting our understanding of which structures depend on MCT8-mediated TH transport throughout life and whether neurodegenerative processes such as Alzheimer's disease (AD) affect local transporter availability. In this study, we systematically mapped MCT8 expression across eight functionally distinct brain regions from 14 aged human body donors. Our multiscale approach combined immunostaining, automated whole-slide image analysis of over 13 million cells, multiplex RNAscope in situ hybridization, stimulated emission depletion (STED) microscopy, and single-nucleus RNA sequencing data analysis. We additionally applied standardized Braak staging to investigate whether AD progression correlates with alterations in MCT8 expression. We demonstrate robust MCT8 expression across brain barriers, glial cells, and in distinct neuronal populations. RNAscope confirmed a strong concordance between SLC16A2 mRNA presence and MCT8 immunoreactivity. STED and confocal microscopy localized MCT8 to plasma membranes, perinuclear regions, and axonal/dendritic compartments, indicating roles in both trans- and intracellular TH transport. MCT8 expression was preserved across Braak stages, with no significant difference between donors with varying degrees of neurofibrillary pathology. Our findings establish a comprehensive cellular and regional framework for MCT8-mediated transport in the human brain, mapping its specific anatomical distribution across regions crucial for motor control and cognitive processing. Stable MCT8 expression across Braak stages suggests that cerebral TH dysregulation in AD likely reflects altered hormone metabolism rather than transporter loss.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149102590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The superior prognostic role of pRB1 over p16 immunohistochemistry as a biomarker in meningiomas.","authors":"Hanna Gött, Jonas Tellermann, Hannes Becker, Christina Fodi, Peter Paßlack, Elgin Hoffmann, Maria Elisa Di Francesco, Daniel J Merk, Jürgen Honegger, Ghazaleh Tabatabai, Marcos Tatagiba, Felix Behling, Jens Schittenhelm","doi":"10.1186/s40478-026-02419-3","DOIUrl":"10.1186/s40478-026-02419-3","url":null,"abstract":"<p><strong>Background: </strong>Despite best clinical management, patients with meningiomas frequently experience tumor recurrence. During recent decades, efforts have been made to improve the prognostic stratification of meningiomas by incorporating molecular data. A subgroup of tumors harboring a homozygous CDKN2A deletion was identified, and a higher risk of tumor progression was observed, suggesting the potential use of cyclin-dependent kinases as biomarkers.</p><p><strong>Material and methods: </strong>In this retrospective single-center study, the immunohistochemical staining for the cyclin-dependent kinases p16, phosphoRB1 (pRB1), CDK4 and CDK6 was analyzed in 1751 paraffin-embedded meningioma samples. For the assessment of p16, CDK4 and CDK6, a semi-quantitative score was applied, whereas an automated quantification tool was used for pRB1. The distribution and association with histopathological results, clinical data and progression-free survival (PFS)-defined by radiographic tumor recurrence-were assessed.</p><p><strong>Results: </strong>Of all meningioma samples, 14.9% (n = 261) expressed p16. Elevated pRB1 levels were found in 34.5% (n = 589) of tumor samples. CDK4 and CDK6 positive staining was observed in 41.9% and 42.2% of cases, respectively. Dichotomous stratification of meningiomas based on p16 and pRB1 expression levels suggested a significant influence on PFS in univariate analyses. Multivariate analysis determined elevated pRB1 expression, WHO grading, extent of resection, adjuvant radiotherapy, male gender, NF2-status and an elevated MIB1 index as independent prognostic factors.</p><p><strong>Conclusions: </strong>High expression of pRB1 is an independent prognostic factor for shorter PFS. The prognostic impact of p16 is mostly attributed to the confounding increase of pRB1 expression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148904963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.","authors":"Leonie Sowoidnich, Aaron L Norman, Florian Gerstner, Josiane K Siemund, Jannik M Buettner, John G Pagiazitis, Vanessa Dreilich, Konstantin Pilz, Dajun Tian, Charlotte J Sumner, Angela Paradis, George Z Mentis, Christian M Simon","doi":"10.1186/s40478-026-02415-7","DOIUrl":"10.1186/s40478-026-02415-7","url":null,"abstract":"<p><p>Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, for which spinal cord sampling emerged as a major contributor. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-associated epigenomic heterogeneity in papillary tumors of the pineal region: a multicenter YoungNOA investigation.","authors":"Lazaros Lazaridis, Xiaomei Zhou, Raphael Bodensohn, Malte Mohme, Julia Onken, Regina von Manitius, Naomi Houedjissin, Tobias Blau, Ilinca Popp, Sarina Agkatsev, Sabine Seidel, Christina Schaub, Maximilian Scheer, Andre Sagerer, Volker Neuschmelting, Davide Tosin, Viktoria Ruf, Michael C Burger, Christoph Oster, Teresa Schmidt, Benjamin Thiele, Jürgen Hench, Stephan Frank, Martin Stuschke, Laurèl Rauschenbach, Stephan Tippelt, Beate Timmermann, Kathy Keyvani, Clemens Seidel, Andrea Tannapfel, Dorothea Miller, Niklas Thon, Joachim P Steinbach, Elke Pfaff, Georg Karpel-Massler, Jörg Felsberg, Guido Reifenberger, Marcos Tatagiba, Ghazaleh Tabatabai, Jens Schittenhelm, Christian Thomas, Martin Hasselblatt, Corinna Seliger, Christoph Kleinschnitz, Ulrich Sure, David Capper, Michael Platten, Felix Behling, Michael Müther, Sied Kebir","doi":"10.1186/s40478-026-02411-x","DOIUrl":"10.1186/s40478-026-02411-x","url":null,"abstract":"<p><strong>Background: </strong>Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear.</p><p><strong>Methods: </strong>We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation.</p><p><strong>Results: </strong>Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7%]) compared with adult tumors (39 of 62 [62.9%]). After adjustment for methylation-based subgroup as well as technical and biological covariates, 2,923 CpG probes were associated with age at a false discovery rate (FDR) threshold below 0.05, and 530 also met the prespecified effect-size threshold. Global methylation summaries were similar between age groups. CNV patterns were dominated by molecular subgroup; adjusted genomic CNV load was not independently associated with pediatric age. In contrast, epiTOC2 intrinsic rate score and the methylation signature represented by the first principal component (PC1) showed age-associated effects independent of molecular subgroup. Methylation-based deconvolution suggested a limited microenvironmental signal, with neutrophil fraction showing the most consistent adjusted association.</p><p><strong>Conclusions: </strong>Adult and pediatric PTPR share the established PTPR-A/PTPR-B framework. Pediatric tumors, particularly within PTPR-B, showed age-associated DNA methylation differences and higher epigenetic mitotic-clock (epiTOC2) scores in this retrospective cohort. These tissue-level associations do not establish clinical risk or treatment implications and require prospective clinical annotation and orthogonal validation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental induction of myelin damage in post-mortem human brain slice cultures.","authors":"Niels Reinder Coenraad Meijns, Gema Muñoz González, Sabine Stolker, Bert T Hart, Bonnie C Plug, Marianna Bugiani, Anita Grootemaat, Nicole van der Wel, Öznur Bilir, Kasra Roya-Kouchaki, Wulin Teo, Peter K Stys, Sophie Hill, Geert J Schenk, Gijs Kooij, Ben Newland, Antonio Luchicchi","doi":"10.1186/s40478-026-02398-5","DOIUrl":"10.1186/s40478-026-02398-5","url":null,"abstract":"<p><p>The mechanisms that drive myelin damage as seen in demyelinating disorders such as multiple sclerosis remain incompletely understood. Much of our current knowledge is derived from animal models, but interspecies differences limit their relevance in the context of human pathology and could explain why various promising therapies failed during clinical translation. Human post-mortem organotypic brain slice cultures provide a unique platform to study human myelin biology, as they preserve genetic, cytoarchitectural, pathological and species-specific context. Here, we evaluated myelin integrity in a human post-mortem organotypic brain slice culture model and experimentally induced focal myelin damage. Human post-mortem organotypic brain slice cultures retain key features throughout the culturing period, but exhibit gradual cellular and myelin loss over time. Myelin fibres within the white matter remain detectable and display preserved structural and chemical integrity up to 13 days in vitro, as indicated by the conserved ultrastructure, paranodal and nodal organization, and stable myelin spectroscopic signature. Topical delivery of lysophosphatidylcholine using cryogel scaffolds enables focal drug administration throughout the full depth of the slice with minimal diffusion into surrounding tissue and induces localized demyelination. Similar focal application of β-scorpion toxin Cn2, a Na_v1.6 channel agonist, induces subtle myelin destabilization. Overall, our results demonstrate human post-mortem organotypic brain slice culture model as an adequate platform for studying myelin damage in a human context.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overactivation of SHH signaling induces a cascade of dedifferentiation and oncogenesis in a new mouse model for choroid plexus carcinoma.","authors":"Levke-Sophie Peter, Lea Altendorf, Karoline Hack, Vanessa Thaden, Carolin Göbel, Beatrix Mahnke, Christian Krebs, Saskia-L Jauch-Speer, Uwe R Kordes, Denise Obrecht-Sturm, Christian Thomas, Ulrich Schüller, Melanie Schoof","doi":"10.1186/s40478-026-02402-y","DOIUrl":"10.1186/s40478-026-02402-y","url":null,"abstract":"<p><p>Choroid Plexus tumors constitute 10-20% of brain tumors in infancy. Among these, Choroid Plexus Carcinomas (CPC) are highly aggressive and result in poor survival. Details on tumor initiation and oncogenic events remain largely unknown, aside from a high prevalence of TP53 mutations and marked chromosomal instability. We generated hGFAP-cre::lsl-MYCN::lsl-Gli2(N)::Tp53^fl/fl mice with recombination activity from embryonic day 13.5 onwards in CNS cells, leading to MYCN and Gli2 activation as well as TP53 inactivation. 84% of the mice developed ventricular tumors within 18 days of life, resembling human CPCs in histology and marker expression. We performed histological and molecular characterization of the resulting tumors and treated tumor cells in vitro. We demonstrate that aberrant Sonic Hedgehog (SHH) signaling during embryonic Choroid Plexus (CP) development triggers a dedifferentiation cascade that reverts mature epithelium to a progenitor-like state. Spatial transcriptomic analysis identifies a distinct cellular hierarchy, where differentiated plexus cells shed their secretory identity to adopt malignant progenitor states. This transformation is accompanied by a transition from multiciliated epithelial cells expressing mature, secretory CP markers to highly proliferative, monociliated progenitors expressing SOX2. This malignant reprogramming activates embryonic developmental programs and induces a critical dependency on cell cycle and DNA repair pathways. Consequently, we identify that these tumor cells cultivated in vitro are vulnerable to ATR and CDK inhibition.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13499314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced microvascular coverage links a hypoxia-associated niche to microglial autophagic dysfunction in Parkinson's disease.","authors":"Hualin Wang, Zhuang Zhu, Zefu Yin, Yao Geng, Yihang Xu, Yi Fan, Kezhong Zhang","doi":"10.1186/s40478-026-02412-w","DOIUrl":"10.1186/s40478-026-02412-w","url":null,"abstract":"<p><p>Microglial hyperactivation contributes to Parkinson's disease (PD) progression, yet the upstream microenvironmental cues that sustain this state remain incompletely understood. While α-synuclein (α-Syn) aggregation is a primary trigger, aging and PD are also associated with microvascular and perfusion abnormalities. However, how vascular-associated hypoxic stress interacts with protein toxicity in microglial fate determination remains unclear. We integrated human single-nucleus RNA sequencing (snRNA-seq) data, a chronic progressive transgenic mouse model (9-month-old A53T), and an in vitro \"double-hit\" model. Neuropathological and immunofluorescence analyses were employed to assess the neurovascular unit and microglial phenotypes. The snRNA-seq analysis of human PD brains revealed a Disease-Associated Microglia (DAM) subset characterized by enrichment of hypoxia and glycolysis pathways, with HIF1A acting as a central node. In vivo, 9-month-old A53T mice exhibited motor deficits and dopaminergic degeneration, accompanied by reduced CD31+ microvascular coverage in the substantia nigra. This reduction in CD31+ vascular coverage was associated with microglial HIF1A accumulation and increased IBA1-defined soma area. In vitro, physical hypoxia amplified α-Syn preformed fibril (PFF)-induced microglial reactivity, intracellular accumulation of phosphorylated α-Syn (p-αSyn). Our study supports a \"double-hit\" model in which hypoxia-associated stress may amplify α-Syn-induced microglial dysfunction through HIF1A-linked metabolic remodeling and impaired autophagy-related protein handling. Targeting neurovascular-immune interactions may offer therapeutic opportunities for advanced PD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"14 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}