Acta Neuropathologica Communications最新文献

{"title":"Demyelinated lesion associated compartmental inflammation in progressive multiple sclerosis brains.","authors":"Liane Najm, Anthony Chomyk, Kaitlyn Cyncynatus, Dimitrios Davalos, Kedar R Mahajan, Bruce D Trapp","doi":"10.1186/s40478-025-02122-9","DOIUrl":"10.1186/s40478-025-02122-9","url":null,"abstract":"<p><p>The pathogenesis of progressive multiple sclerosis (PMS) involves aggregates of peripheral and innate immune cells that are collectively referred to as compartmental inflammation. Sites include the meninges, perivascular spaces of vessels, choroid plexus, and borders of demyelinated lesions. Iron-laden activated microglia/macrophages that border cerebral white matter (WM) lesions appear as paramagnetic rims (PRLs) on magnetic resonance imaging. PRLs have been associated with lesion expansion and are considered as a target of brain-penetrable therapies in people with MS. Less is known about inflammatory compartments Bordering cortical lesions. The objective of this retrospective study is to describe the location and morphology of MHC Class II-positive cells in 334 demyelinated lesions from 22 PMS brains. Activated microglia bordered Type III subpial lesions (cortical layers I through III demyelinated) and cortical portions of leukocortical lesions. Activated microglia/macrophages lined the border of chronic active WM lesions, WM portions of leukocortical lesions, and Type IV subpial lesions (all six cortical layers demyelinated). Type IV subpial lesions were lined by activated microglia/macrophages that resided in subcortical WM and were always contiguous with Type III subpial lesions. The location in WM or cortex, rather than lesion type, determined the cellular composition of inflammatory compartments. Since the majority of subpial lesions stop at cortical layer IV and Type IV subpial lesions do not invade subcortical WM, compartments bordering subpial lesions are often associated with lesion stability. Iron was enriched in a subpopulation of inflammatory compartments bordering WM and Type IV subpial lesions, as well as at the border of myelinated cortex and subcortical WM. These myelinated borders were not enriched in microglia and iron was diffusely distributed, providing evidence that iron enrichment is not always associated with lesion expansion nor compartmental inflammation. These data will aid in designing imaging outcome measures for clinical trials targeting inflammatory compartments in PMS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"204"},"PeriodicalIF":5.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190619","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":"Telomere-driven senescence accelerates tau pathology, neuroinflammation and neurodegeneration in a tauopathy mouse model.","authors":"Debora Palomares, Axelle A T Vanparys, Joana Jorgji, Esther Paître, Pascal Kienlen-Campard, Nuria Suelves","doi":"10.1186/s40478-025-02118-5","DOIUrl":"10.1186/s40478-025-02118-5","url":null,"abstract":"<p><p>The connection between aging and neurodegenerative pathologies like Alzheimer's disease (AD) has long been recognized, with senescent brain cells building up in the brains of AD patients. A causal link has been established between senescence and AD-related tauopathy, but the mechanisms underlying these pathological changes remain largely unknown. To unravel the precise role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc^-/-) mouse model of telomere-induced senescence with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, an array of biochemical and molecular techniques was applied to investigate the expression of tau-related neuropathological features within a senescent context. Our results showed that the brains of 6- and 9-month-old Terc^-/- mice exhibit significant telomere attrition and signs of cellular senescence. Additionally, we found evidence that the introduction of a senescent phenotype in a tauopathy mouse model results in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this leads to enhanced tau truncation and aggregation, accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. Overall, these findings place senescence as a key upstream regulator of tau pathology and tau-related neurodegeneration, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"206"},"PeriodicalIF":5.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190591","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":"Current states in understanding oligodendroglia-mediated neurological issues in neurofibromatosis type 1 (NF1).","authors":"Benjamin E Aghoghovwia, Cheng-En Shen, Sabiha Bano, Nandini Shyamala, Alesandra Echeandia Marrero, Khushboo Irshad, Samer Sharafaldin, Nicole M Brossier, Yuan Pan","doi":"10.1186/s40478-025-02119-4","DOIUrl":"10.1186/s40478-025-02119-4","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is among the most common neurogenetic disorders and is associated with an increased risk of developing tumors in the nervous system. Additionally, up to 80% of patients with NF1 experience neurological complications, including deficits in attention, memory, and executive function. Significant effort has been dedicated to studying how NF1 mutations autonomously dysregulate neuronal function. Increasing evidence indicates that NF1 mutations also dysregulate the oligodendroglial lineage that contributes to neurological issues in NF1. Here, we summarize our current understanding of how NF1 mutations impact the oligodendroglial lineage homeostasis and plasticity. We also discuss gaps in knowledge, potential therapeutic strategies, and future directions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"202"},"PeriodicalIF":5.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190602","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":"Distinct spatial transcriptomic patterns of substantia Nigra in Parkinson disease and Parkinsonian subtype of multiple system atrophy.","authors":"Jung Hwan Shin, Karoliina Eliisa Ruhno, Chaewon Shin, Hyun Je Kim, Soo Jeong Nam, Sun Ju Chung, Ji Hwan Moon, Han-Joon Kim","doi":"10.1186/s40478-025-02107-8","DOIUrl":"10.1186/s40478-025-02107-8","url":null,"abstract":"<p><p>To investigate transcriptomic signatures of Parkinson's disease (PD) and the Parkinsonian subtype of Multiple System Atrophy (MSA-P) in substantia nigra pars compacta (SNpc), we conducted transcriptome analysis using in-situ hybridization on paraffin-embedded SNpc tissues from post-mortem brains. The study included 2 MSA-P patients, 2 PD patients, and 2 healthy controls (HC), with 12 regions of interest (ROIs) selected from the dorsal to ventral and medial to lateral aspects of the SNpc. A total of 72 ROIs from 6 participants were analyzed, and differentially expressed genes (DEGs) were identified by comparing MSA-P, PD and HC groups. The MSA-P group showed 88 upregulated DEGs and 326 downregulated DEGs (adjusted 𝑝<0.05) compared to HC. The downregulated DEGs were significantly enriched in pathways related to ribosomal translation, immune processes, mitochondrial function, and autophagy. Notably, the dorsomedial quadrant was uniquely linked to antigen presentation, while other quadrants showed downregulation of protein synthesis. The PD group exhibited 165 upregulated DEGs and 350 downregulated DEGs (adjusted 𝑝<0.05) compared to HC, with downregulated DEGs associated with ribosomal translation, mitochondrial function, and the ubiquitin-proteasome system. In both MSA-P and PD, the upregulated DEGs were not associated with any pathways or biological process in gene enrichment analysis. In network propagation analysis, amyloid precursor protein was the most significant network hub among DEGs in both MSA-P and PD. Comparing the transcriptomic signatures of SNpc between MSA-P and PD, we found immune/inflammation, mitochondrial function and neural signaling related genes were significantly downregulated in MSA-P compared to PD. Overall, the transcriptomic signature of the SNpc in MSA-P and PD revealed overlapping but distinct features, including alterations in protein synthesis, immune processes, mitochondrial function, and protein degradation systems. Future studies with larger cohorts and functional validation are needed to further elucidate these findings.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"193"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135969","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":"RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease.","authors":"Miao-Jin Ji, Yun Li, Jiao Yang, Kangjunjie Wang, Shuning Sang, Hong Yang, Chenhao Tian, Xin Tang, Ji-Heng Cai, Tianhan He, Cheng Zhang, Huanyao Tang, Tiantao Cui, Xinran Meng, Xiang Cao, Jiaqi Zhu, Jie Wang, Jun-Li Cao, Daming Gao, Chao Liu","doi":"10.1186/s40478-025-02115-8","DOIUrl":"10.1186/s40478-025-02115-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer's disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"198"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135947","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":"Cell-cell communication dysregulation in tuberous sclerosis complex cortical tubers and focal cortical dysplasia.","authors":"Mirte Scheper, Jasper J Anink, Floor E Jansen, Wim Van Hecke, Angelika Mühlebner, James D Mills, Eleonora Aronica","doi":"10.1186/s40478-025-02113-w","DOIUrl":"10.1186/s40478-025-02113-w","url":null,"abstract":"<p><p>Malformations of cortical development are manifestations of mTORopathies, including tubers in context of Tuberous Sclerosis Complex (TSC) cortical tubers and Focal Cortical Dysplasia (FCD), and are associated with epilepsy, often accompanied by comorbidities such as autism spectrum disorder (ASD). This study aims to investigate the cell-type-specific transcriptional alterations and disrupted intercellular communication networks in mTORopathies, focusing on their implications for cortical network dysfunction. Using single-cell RNA sequencing, we identified 33 transcriptionally distinct cell clusters across control and pathological samples, including neuronal, glial, and endothelial populations. Our analysis revealed disease-specific changes, such as the loss of certain glutamatergic and microglial clusters in cortical tubers (TSC), MTOR_FCD and DEPDC5_FCD, and the presence of a unique endothelial cluster in pathological samples. Pathway enrichment analysis highlighted the critical role of synaptic signaling, axonogenesis, and neuroimmune regulation in these disorders. Additionally, cell-cell communication network analysis demonstrated disrupted interactions between neuron-astrocyte, astrocyte-OPC, and microglia-neuron across mTORopathies. We found that the neurexins-neuroligins (NRXN-NLGN) signaling pathway, crucial for synapse formation and stability, was altered in both glutamatergic and GABAergic neurons, reflecting dysregulated synaptic plasticity and impaired neuron-glia communication. These findings provide novel insights into the molecular underpinnings of mTORopathies and suggest potential therapeutic targets to restore cellular communication and synaptic function in these disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"196"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135971","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":"Facilitated α-synuclein oligomer sharing among glial cells by a centrally acting connexin inhibitor attenuates a rapidly progressive multiple system atrophy-cerebellar type model by reducing the neuronal α-synuclein burden.","authors":"Masaya Harada, Katsuhisa Masaki, Tatsunori Tanaka, Hiroaki Sekiya, Dai Matsuse, Hiroo Yamaguchi, Yuji Nishimura, Ezgi Ozdemir Takase, Eizo Tanaka, Yuu-Ichi Kira, Kei Fujishima, Eriko Matsuo, Ryo Yamasaki, Dennis W Dickson, Akio Suzumura, Takayuki Taniwaki, Tomoaki Hoshino, Noriko Isobe, Hideyuki Takeuchi, Jun-Ichi Kira","doi":"10.1186/s40478-025-02116-7","DOIUrl":"10.1186/s40478-025-02116-7","url":null,"abstract":"<p><p>Glial connexins (Cxs) that make up astrocyte/oligodendrocyte gap junctions are extensively altered in multiple system atrophy-cerebellar type (MSA-C). Here, we investigated how Cx alterations affect the propagation of α-synuclein (α-syn) oligomers and phosphorylated (p)-α-syn aggregates in MSA-C using a centrally acting pan-Cx blocker, INI-0602. Our Plp1-tTA::tetO-SNCA*A53T transgenic (Tg) mice express mutant human A53T α-syn in oligodendrocytes after dietary doxycycline withdrawal at 8 weeks of age; they typically develop progressive ataxia around 22 weeks and die by 30 weeks. These Tg mice were intraperitoneally administered INI-0602 or vehicle from 18 to 26 weeks of age. Proximity ligation assay demonstrated that α-syn oligomers in small glial cells of the brainstem/cerebellum peaked at 10 weeks and maintained similar levels thereafter. In neuropil, α-syn oligomers appeared at 10 weeks, peaked at 16 weeks, and decreased from 24 weeks. In large cells (neuronal somata or reactive astrocytes), α-syn oligomers continuously accumulated from 10 to 30 weeks. By contrast, p-α-syn accumulated predominantly in oligodendrocytes from 24 to 30 weeks and later appeared in astrocytes, microglia, and neurons. Notably, double staining revealed that α-syn oligomers and p-α-syn were rarely colocalised. In the lesion centre with abundant p-α-syn deposits, both oligodendrocytic Cx47/Cx32 and astrocytic Cx43/Cx30 expression were extensively lost. Conversely, at the leading edges, Cx43 was upregulated despite Cx47 loss, resulting in abundant Cx43 hemichannels. INI-0602 suppressed increased hemichannel activity in the leading edges in acute slice culture and attenuated MSA-C and glial inflammation-thereby preserving Cx gap junctions-in Tg mice. INI-0602 treatment reduced neuronal α-syn oligomers and p-α-syn aggregates but facilitated α-syn oligomer dissemination throughout glial cells and neuropil. In human MSA-C, distinct distribution patterns between α-syn oligomers and p-α-syn deposits were also observed. Thus, increased sharing of α-syn oligomers via preserved Cx gap junctions may help attenuate MSA-C pathology by reducing neuronal α-syn aggregates.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"197"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135932","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":"Two molecular subtypes of skull base meningiomas with extracranial extension.","authors":"Yudai Hirano, Motoyuki Umekawa, Satoru Miyawaki, Yu Sakai, Hirotaka Hasegawa, Yu Teranishi, Shotaro Ogawa, Daisuke Komura, Hiroto Katoh, Masako Ikemura, Hideaki Ono, Tetsuo Ushiku, Shumpei Ishikawa, Nobuhito Saito","doi":"10.1186/s40478-025-02111-y","DOIUrl":"10.1186/s40478-025-02111-y","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"201"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237682","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":"Tissue-type plasminogen activator expression by endothelial cells and oligodendrocytes is required for proper CNS myelination.","authors":"Barbara Delaunay-Piednoir, Elsa Pouettre, Olivier Etard, Didier Goux, Erwan Baudron, Fabian Docagne, Eric Maubert, Denis Vivien, Isabelle Bardou","doi":"10.1186/s40478-025-02110-z","DOIUrl":"10.1186/s40478-025-02110-z","url":null,"abstract":"<p><p>Oligodendrocytes form myelin sheaths, a process regulated by intrinsic and extrinsic signals. Endothelial derived-tissue-type plasminogen activator (tPA) has been previously recognized for its role in aiding oligodendrocyte migration during (re)myelination. Moreover, it is well established that oligodendrocytes express de novo tPA following myelin damage, possibly reflecting the initiation of a regenerative program. However, its role in differentiation and myelination has remained unclear. This study aims to uncover the role of endothelial- and oligodendrocytes-derived tPA in developmental myelination. It appears that tPA is transiently expressed in myelinating oligodendrocytes in mice and humans. tPA deficiency delays oligodendrocyte maturation and causes persistent myelin defects, leading to motor impairments. Endothelial-derived tPA promotes myelin compaction, while oligodendrocyte-derived tPA supports myelin growth. These findings, along with previous research, highlight shared molecular mechanisms between developmental myelination and remyelination. Moreover, we highlight tPA's dual roles in myelination. Thus, tPA-deficient mice could serve as a valuable model to study dysmyelinating diseases and to explore potential avenues for future therapeutic strategies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"192"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135919","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 mouse model of stereotactic radiosurgery-induced neuroinflammation and blood-brain barrier compromise.","authors":"Roberto J Alcazar-Felix, Lin Cheng, Abhinav Srinath, Akash Bindal, David Tieri, Diana Vera-Cruz, Madison Yuan, Sammy Allaw, Nitha Aima Muntu, Dominic Montas, András Piffkó, Erik Pearson, Bader Ali, Peter Pytel, Issam A Awad, Sean P Polster","doi":"10.1186/s40478-025-02112-x","DOIUrl":"10.1186/s40478-025-02112-x","url":null,"abstract":"<p><p>Stereotactic radiosurgery (SRS) is a procedure that delivers high-dose single fraction, targeted radiation to treat brain pathologies. Brain radiation necrosis is a significant side effect of SRS, resulting in severe clinical sequelae such as seizure, hemorrhage, stroke, and neurological deficit. While focused radiation causes DNA damage and cell death, radiation necrosis is mostly mediated by vascular injury. Yet the effects of SRS on the neurovascular unit (NVU) cells-microglia, astrocytes, and endothelial cells-remain poorly understood. This study establishes a mouse SRS model using 15 to 60 Gy to characterize NVU stress, providing histological and transcriptomic profiles of radiation-induced damage. Our findings demonstrate blood-brain-barrier (BBB) disruption, inflammatory cell infiltration, and microvascular pathology. Spatial transcriptomics identified differentially expressed genes and cell-cell communication across NVU components, revealing a coordinated stress response involving immune modulation, barrier integrity, and tissue remodeling pathways. This model provides a mechanistic framework for developing strategies to mitigate BBB and NVU stress.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"195"},"PeriodicalIF":5.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12461976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135976","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}