Brain Pathology最新文献

{"title":"Olfactory proteomics reveals the capacity of the HDAC1 inhibitor pyroxamide to halt the α-synuclein preformed fibrils-induced damage in nasal epithelial, microglial and dopaminergic neuronal cell lines.","authors":"Paz Cartas-Cejudo, Marina De Miguel, Leire Extramiana, Mercedes Lachén-Montes, Silvia Romero-Murillo, Djordje Gveric, Joaquín Fernández-Irigoyen, Enrique Santamaría","doi":"10.1111/bpa.70140","DOIUrl":"10.1111/bpa.70140","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most common neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons originating in the substantia nigra (SN) pars compacta and projecting to other brain regions, giving rise to motor and non-motor symptoms. Despite significant progress in understanding the molecular and cellular disruptions associated with PD, there remains an unmet clinical need for effective therapies. In this study, proteomic analysis of the olfactory tract (OT) in controls with no known neurological history (n = 17) and PD subjects (n = 21) revealed Lewy body disease (LBD) stage-dependent proteostatic impairment, accompanied by progressive modulation of the alpha-synuclein (α-syn) functional interactome. Differential OT omic profiles were used in a computational drug repurposing approach, revealing the HDAC1 inhibitor pyroxamide as one of the top drug candidates with in silico potential to restore altered OT omic profiles. To explore the potential therapeutic effects of pyroxamide, in vitro assays were performed using α-syn preformed fibrils (PFFs). Pyroxamide treatment reduced α-syn PFFs-induced toxicity in olfactory epithelial, microglial and dopaminergic neuronal cell lines, producing a protective effect against hydrogen peroxide-induced damage exclusively in brain-derived cell types. Mechanistically, the mitigating effects of pyroxamide were attributable, at least in part, to the regulation of Bax-1 and sirtuin 1 (SIRT1) protein expression, along with alterations in the mRNA levels of NEF2L2, IL1B, and TNF-α. These findings confirm the suitability of omics profiles in drug repurposing workflows against PD, offering valuable insights into the potential of HDAC1 inhibitors in the therapeutic pipeline of PD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70140"},"PeriodicalIF":5.0,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863320","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":"AOSNP-ADAPTR resource level-based recommendations on practical diagnostic strategies for medulloblastomas and other embryonal tumors.","authors":"Chitra Sarkar, Maysa Al-Hussaini, Vani Santosh, Vaishali Suri, Sung-Hye Park, Yue-Shan Piao, Tarik Tihan, Ho-Keung Ng, Michael Buckland, Rakesh Jalali, Yonehiro Kanemura, Pieter Wesseling, Takashi Komori","doi":"10.1111/bpa.70136","DOIUrl":"10.1111/bpa.70136","url":null,"abstract":"<p><p>WHO CNS5 mandates integrated histo-molecular classification of medulloblastomas (MBs) and other CNS embryonal tumors. However, advanced molecular diagnostics remain inaccessible in many low- and lower-middle-income countries (LICs/LMICs), limiting implementation of molecularly informed risk stratification and therapy. The ADAPTR group (Adapting Diagnostic Approaches for Practical Taxonomy in Resource-Restrained Regions) is an initiative of the Asian Oceanian Society of Neuropathology (AOSNP) and aims to provide practical guidelines for CNS tumor diagnostics at various levels of pathology resource restraints. In this manuscript, we propose a practical approach to diagnosis of MBs and other CNS embryonal tumors based on ADAPTR resource levels (RLs). The emphasis is mainly on using histopathological approaches with immunohistochemistry (IHC), while molecular testing recommendations are categorized as \"can be considered,\" \"highly recommended\" or \"obligatory\" to reach the next level diagnosis. In each RL, either a WHO CNS5 diagnosis with an accompanying CNS WHO grade or an ADAPTR descriptive diagnosis with an associated ADAPTR histologic grade and comment is provided, depending on the context. \"Histology-oriented integrated diagnosis format\" for each tumor type at different RLs along with diagnostic flow charts has been generated to suit these RLs. For MBs, at RL I-II, diagnosis relies on histopathology and basic IHC with structured ADAPTR descriptive reporting. At RL III, surrogate IHC panels enable assignment to WNT-activated, SHH-activated and non-WNT/non-SHH groups, facilitating clinically actionable risk stratification. RL IV incorporates targeted molecular tests (e.g., MYC/MYCN amplification, CTNNB1 and TP53 mutations) for prognostic refinement. RL V supports comprehensive molecular classification through next-generation sequencing and DNA methylation profiling. Parallel RL-based algorithms are proposed for other CNS embryonal tumors, incorporating essential surrogate and confirmatory markers. These AOSNP-ADAPTR recommendations provide a practical adaptation of WHO CNS5 guidelines suited to routine diagnosis in resource-restrained regions. This model promotes equitable, risk-adapted care while supporting progressive strengthening of global neuropathology capacity.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70136"},"PeriodicalIF":5.0,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849693","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":"Brain calcification-associated JAM2 pathogenic mutations impair JAM2-JAM3 tight junction structure and the blood-brain barrier integrity.","authors":"Dehao Yang, Lebo Wang, Chenxin Ying, Yihua Shi, Yuru Guo, Haotian Wang, Xinhui Chen, Yaoting Wang, Xinchen Wang, Fan Zhang, Xiaosheng Zheng, Yiling Chen, Haoyu Wang, Zhiru Lin, Jiaxiang Li, Haibin Xia, Jiawen Chen, Feng Fu, Bo Wang, Sheng Wu, Ping Wang, Fei Xie, Zhidong Cen, Zhiping Wang, Wei Luo","doi":"10.1111/bpa.70139","DOIUrl":"10.1111/bpa.70139","url":null,"abstract":"<p><p>Primary brain calcification (PBC) is a neurodegenerative disorder characterized by bilateral brain calcification. JAM2 is a PBC causative gene, encoding the tight junction protein JAM2 and critical for blood-brain barrier (BBB) integrity, with an uncertain pathogenic mechanism. We analyzed two JAM2 missense mutations identified in PBC patients using plasmid constructs, immunoprecipitation, flow cytometry, and structural modeling. A Jam2 knockout (KO) mouse model was generated to assess behavioral deficits, brain calcification, and BBB integrity via histology, Evans blue assay, and in situ hybridization. JAM2-W108C mutants showed abnormal localization, while JAM2-R108H specifically disrupted JAM2-JAM3 interaction, mirroring the pathogenic JAM3-E116K mutation. Jam2 KO mice exhibited midbrain calcification (von Kossa staining) and motor impairments (rotarod/beam-walking tests) at 6-12 months. JAM2 and JAM3 co-localized in brain endothelial cells, and KO mice demonstrated BBB leakage (Evans blue extravasation). The main pathogenic mechanism of JAM2-PBC should be associated with the impaired JAM2-JAM3 heterodimer formation, compromising tight junctions and BBB integrity. Our study indicates JAM2-JAM3 interaction as a potential therapeutic target for PBC and related brain calcification disorders.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70139"},"PeriodicalIF":5.0,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839261","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":"α-Synuclein strain homogeneity in multiple system atrophy subtypes.","authors":"Heather H C Lau, Nicholas R G Silver, Surabhi Mehra, Raphaella W L So, Le Yao Li, Alison Mao, Erica Stuart, Cian Schmitt-Ulms, Bradley T Hyman, Martin Ingelsson, Joel C Watts","doi":"10.1111/bpa.70134","DOIUrl":"https://doi.org/10.1111/bpa.70134","url":null,"abstract":"<p><p>Conformationally distinct \"strains\" of α-synuclein aggregates are believed to contribute to the clinical and pathological diversity observed among synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease. Cases of MSA can be classified into two distinct subtypes: the cerebellar variant, MSA-C, and the parkinsonian variant, MSA-P, as determined by differences in their clinical and/or neuropathological presentations. To assess whether distinct α-synuclein strains may be present in individuals with MSA-C versus MSA-P, we characterized the conformational and seeding properties of α-synuclein aggregates in various brain regions from MSA-C and MSA-P patients and performed propagation studies in M83 transgenic mice. Biochemical fingerprinting of α-synuclein aggregates using limited proteolysis and a conformational stability assay failed to reveal differences between MSA-C and MSA-P either before or after propagation in mice. Similarly, using brain extracts from either MSA patients or MSA-inoculated mice, MSA-C and MSA-P α-synuclein aggregates exhibited indistinguishable seeding attributes in a seed amplification assay. Finally, no differences were observed in either the kinetics of disease progression or the extent of cerebral α-synuclein deposition in M83 mice inoculated with either MSA-C or MSA-P, regardless of the brain region from which the injected α-synuclein aggregates were derived. These results suggest that MSA subtypes are unlikely to arise because of distinct α-synuclein strains. Instead, our findings support a model in which the same α-synuclein strain initially forms in different brain regions, leading to differences in disease manifestation.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70134"},"PeriodicalIF":5.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757718","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":"Artificial intelligence-based 3D segmentation of tangle-associated TDP-43 in neurodegeneration.","authors":"Gokhan Uruk, Hossam Youssef, Rodolfo G Gatto, Nadia Hossain, Jennifer L Whitwell, Robert R Reichard, Keith A Josephs","doi":"10.1111/bpa.70131","DOIUrl":"10.1111/bpa.70131","url":null,"abstract":"<p><p>TAR DNA-binding protein 43 (TDP-43) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age-related tauopathy (PART). TDP-43 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP-43 are yet to be elucidated. We investigate relationships between TDP-43 inclusions and the tangle maturation continuum in AD, PART, and co-pathologies by multiplex immunostaining combined with artificial intelligence (AI)-based segmentation via object recognition, reconstruction, and quantification. We performed anti-phosphorylated TDP-43 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP-43 (PART-TDP), five cases with high likelihood AD and TDP-43 (AD-TDP), and four cases of high likelihood AD with TDP-43 and Lewy Body disease (AD-TDP-LBD). Confocal imaging was taken from eight regions: amygdala (amygdala-BL and amygdala-CM) and hippocampus (Cornu Ammonis (CA)-1, CA2/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP-43 (TAT) inclusions. TATs, which were either identified by pTDP-43 and AT8 or pTDP-43 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre-TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre-TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI-based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP-43, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region-specific dynamics in the neurodegenerative processes of PART and AD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70131"},"PeriodicalIF":5.0,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688458","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":"Molecular heterogeneity and prognostic biomarkers in primary meningeal melanocytic tumors.","authors":"Rosina Paterra, Monica Patanè, Anna Stroppa, Gianluca Marucci, Serena Ammendola, Sofia Asioli, Valeria Barresi","doi":"10.1111/bpa.70133","DOIUrl":"10.1111/bpa.70133","url":null,"abstract":"<p><p>Primary meningeal melanocytic tumors (PMMTs) are rare neoplasms currently stratified by the World Health Organization (WHO) into three grades of malignancy based exclusively on histopathological criteria, while the prognostic significance of molecular alterations remains poorly defined. This study aimed to investigate the prognostic relevance of histopathological and molecular features in PMMTs and to assess the diagnostic utility of immunohistochemical and molecular markers for distinguishing PMMTs from malignant melanotic nerve sheath tumors (MMNSTs). Thirty-six primary central nervous system (CNS) melanocytic tumors, including 24 PMMTs (10 grade 1, 12 grade 2, and 2 grade 3) and 12 MMNSTs, were analyzed through integrated histopathological, immunohistochemical, genetic, and epigenetic characterization. Among grade 2 PMMTs, descriptively defined CNS-invasive otherwise benign melanocytomas defined a clinically favorable subgroup, whereas SF3B1 mutations and chromosome 8q gains were associated with higher recurrence rates and shorter recurrence-free survival. Losses of chromosome 17 or 21q were observed exclusively in MMNSTs, supporting their potential diagnostic utility in distinguishing MMNSTs from PMMTs. These findings demonstrate biological heterogeneity among intermediate-grade PMMTs and identify molecular markers associated with adverse clinical outcomes. Integrated histopathological and molecular characterization may enhance prognostic stratification and diagnostic accuracy in primary CNS melanocytic tumors.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70133"},"PeriodicalIF":5.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683457","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 frontal lobe mass in a 6-year-old girl.","authors":"Francesca S Vacca, Aaron Mochizuki, Smruti K Patel, Blaise Jones, Somak Roy, Kirti Gupta","doi":"10.1111/bpa.70132","DOIUrl":"10.1111/bpa.70132","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70132"},"PeriodicalIF":5.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13447050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683492","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":"Brain metastasis-associated fibroblasts shape the tumour microenvironment to enhance cancer cell invasion.","authors":"Barbora Výmolová, Lucie Pfeiferová, Tadeáš Karel Smetana, Petr Výmola, Nikola Ternerová, Michal Zubaľ, Michal Kolář, Jana Šáchová, Soňa Gyönyörová, Eva Balážiová, Magdalena Houdová Megová, Jakub Červenka, Helena Kupcová Skalníková, Michal Španko, Karel Smetana, Lukáš Lacina, David Netuka, Robert Tomáš, Petr Bušek, Aleksi Šedo","doi":"10.1111/bpa.70129","DOIUrl":"10.1111/bpa.70129","url":null,"abstract":"<p><p>Brain metastases (BrM) are a frequent and life-threatening complication of solid tumours, with lung cancer representing their most common source. While cancer-associated fibroblasts (CAFs) are well-established contributors to tumour progression in many extracranial malignancies, their presence and function within the brain tumour microenvironment, where fibroblasts have long been considered scarce or absent, remain poorly understood. Here, we isolated and characterised fibroblast-like cells from 13 human BrMs of diverse origins. These BrM-associated CAFs (BrM-CAFs) expressed canonical CAF markers and showed reduced proliferation and increased senescence compared to normal fibroblasts. Their transcriptome was enriched for extracellular matrix (ECM)-related genes, including multiple collagens, fibronectin, and matrix-remodelling enzymes. In vitro, BrM-CAFs produced a fibrillar ECM, and in BrM tissues, their abundance was associated with collagen I and fibronectin deposition. Transcriptomic, proteomic, and secretome analyses further revealed that BrM-CAFs produce multiple cytokines, chemokines, and growth factors that promote cell motility. BrM-CAF conditioned medium promoted both monocyte migration and the migration of cancer cells, including established cell lines and patient-derived lung cancer BrM cells; monocyte migration was partially reduced by inhibition of CCL2/CCR2 signalling, whereas blocking CXCL12, CXCL16, or CX3CL1 attenuated BrM-CAF-induced cancer cell migration. Beyond these effects on migration, exposure to BrM-CAFs increased cancer cell invasion in transwell and heterotypic 3D spheroid assays. In contrast, their effects on cancer cell proliferation were limited and did not indicate a growth-promoting role. Exposure to BrM-CAFs was also associated with increased expression of interferon-stimulated genes in cancer cells. Together, our findings support a role for BrM-CAFs in shaping the brain metastatic microenvironment through ECM remodelling and the secretion of pro-migratory mediators, promoting monocyte and cancer cell migration and enhancing cancer cell invasion. These data identify BrM-CAFs as active stromal participants in BrM biology and support further investigation of their biological, diagnostic, and therapeutic relevance.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70129"},"PeriodicalIF":5.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683451","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 30-year-old woman with progressive lower extremity sensory loss and weakness.","authors":"Daniel W Griepp, Chia-Ming Lee, Jeffrey P Turnbull, Sean P Ferris, Prashant S Kelkar","doi":"10.1111/bpa.70130","DOIUrl":"10.1111/bpa.70130","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70130"},"PeriodicalIF":5.0,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668219","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":"Associations between TMEM106B C-terminal fragment aggregation, age, and TDP-43 or tau pathology","authors":"Albert Acewicz,&nbsp;Sylwia Tarka,&nbsp;Michał Grzegorczyk,&nbsp;Radosław Rzepliński,&nbsp;Teresa Wierzba-Bobrowicz,&nbsp;Tomasz Stępień","doi":"10.1111/bpa.70090","DOIUrl":"10.1111/bpa.70090","url":null,"abstract":"<p>Transmembrane protein 106B (TMEM106B) is a lysosomal glycoprotein whose genetic polymorphisms contribute to the severity of neurodegenerative disorders associated with TDP-43 pathology. Recent studies have revealed that TMEM106B can form amyloid filaments composed of C-terminal fragments (CTFs) in the human brain. In the present study, we explored the relationships between TMEM106B, age, TDP-43, and tau aggregates, and their roles in neurodegeneration. We used immunohistochemistry with an antibody against CTFs of TMEM106B on postmortem human brain fragments (amygdala, hippocampus, temporal cortex, frontal cortex, and basal ganglia) from patients with and without TDP-43/tau pathology at different ages (6–94 years) and with different neurological conditions (subacute sclerosing panencephalitis, Alzheimer's disease, frontotemporal lobar degeneration, and neurologically healthy subjects). Our results revealed that TMEM106B CTF fibrillization is a common, nonspecific, diffuse, and age-dependent phenomenon (appearing after &gt;52 years of age) that affects neurons and neuroglia (most numerous in astrocytes and oligodendrocytes) and broad neuroanatomical regions (most severe in the temporal cortex). We did not find TMEM106B CTF aggregates in young subjects with TDP-43/tau pathology (with subacute sclerosing panencephalitis), but we revealed differences in TMEM106B CTF fibrillization between Alzheimer's disease without TDP-43 pathology, frontotemporal lobar degeneration with TDP-43 pathology, and older healthy subjects without TDP-43/tau pathology. Our results suggest that TMEM106B CTF aggregation is an age-dependent phenomenon and may have a weak association with TDP-43 or tau pathology, shedding new light on the complex relationships among TMEM106B, TDP-43, and tau and the unclear role of TMEM106B fibril formation in the neurodegeneration process.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627241","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}