Acta Neuropathologica Communications最新文献

{"title":"The modulation of the blood-brain barrier by focused ultrasound stimulates oligodendrogenesis.","authors":"Kate Noseworthy, Joseph Silburt, Alessia Apa, Luis Fernando Rubio-Atonal, Sheng-Kai Wu, Carol Schuurmans, Kullervo Hynynen, Isabelle Aubert","doi":"10.1186/s40478-026-02364-1","DOIUrl":"10.1186/s40478-026-02364-1","url":null,"abstract":"<p><p>Focused ultrasound (FUS) combined with intravenous microbubbles (MB) enables precise and reversible modulation of the blood-brain barrier (BBB) to enhance the delivery of therapeutics from the blood to targeted brain areas. Beyond this application, we discovered over a decade ago that FUS-BBB modulation, without the addition of exogenous therapeutics, activates endogenous regenerative events, \"most notably\" hippocampal neurogenesis. Here, we investigate the effects of FUS on oligodendrogenesis, a key process for myelination and white matter integrity. In adult mice, we targeted FUS-BBB modulation unilaterally to the hippocampus. The proliferation of oligodendrocyte precursor cells (OPCs) was quantified at 1, 4, 7, and 10 days post-treatment and myelinating oligodendrocytes were assessed at 30 days. At 1 and 4 days post-sonication, the proliferation of hippocampal OPCs increased by 6.8-fold and 2.3-fold, respectively; this resulted in a 5.3-fold increase in myelinating oligodendrocytes one month later. Next, we tested the robustness of FUS-induced oligodendrogenesis using an independent experimental design and targeting the striatum in a separate cohort of mice. The proliferation of striatal OPCs increased by 3.9-fold at 7 days post-FUS. This led to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment, as observed in the hippocampus. Finally, we found that treatments at the same FUS parameters but without MB and without altering the BBB, did not lead to the proliferation of OPCs or oligodendrogenesis. Therefore, with these FUS parameters, MB-induced BBB modulation emerged as a key factor that promoted oligodendrogenesis. Given the long-validated application of FUS-BBB modulation for drug delivery, the additional stimulation of oligodendrogenesis broadens the therapeutic potential of this modality for white matter repair.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-disease LC-MS/MS plasma proteomics identifies reproducible shared and disease-enriched biomarker signatures in neurodegenerative disorders.","authors":"Youngtae Choi, Shinrye Lee, Janbolat Ashim, Wookyung Yu, Eunji Cho, Ho-Won Lee, Jin-Sung Park, Jong Hyuk Yoon, Hyung-Jun Kim, Mookyung Cheon","doi":"10.1186/s40478-026-02377-w","DOIUrl":"10.1186/s40478-026-02377-w","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417661","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":"Integrated proteogenomic profiling reveals coordinated differential expression signatures during neuroinflammation.","authors":"Elena Prepoudis, Sabina Pfister, Andreas Hofmann, Marc Altorfer, Marco Catalano, Miriam Sindelar, Pamela Ramseier, Frédérique Lafossas, Sarah Tisserand, Tobias Junt, Anna Schubart, Giuseppe Locatelli, Elizaveta Solovyeva","doi":"10.1186/s40478-026-02365-0","DOIUrl":"10.1186/s40478-026-02365-0","url":null,"abstract":"<p><strong>Background: </strong>Experimental autoimmune encephalomyelitis (EAE) is a key model of autoimmune neuroinflammation, yet an integrated characterization of transcriptional and proteomic dysregulation of the CNS has been missing.</p><p><strong>Methods: </strong>In this study, we performed deep proteogenomic profiling of the spinal cord from mice induced with EAE during acute disease by combining RNA-seq (GEO, GSE330115) and LC-MS/MS (PRIDE, PXD078146).</p><p><strong>Results: </strong>We identified extensive upregulation of innate and adaptive immune response signatures alongside concordant downregulation of neuronal, synaptic, and mitochondrial pathways. Despite expected divergence as reported in previous studies discussing neuroinflammation models, log₂ fold changes and pathway enrichment scores showed high concordance between both gene product levels (R_p = 0.867, p < 2.2 × 10⁻1⁶, 95% CI [0.859, 0.874]). Loss of synaptic and metabolic integrity was predominantly observed at the protein level, whereas transcriptomics alone underestimated these structural deficits. In addition to inflammatory changes within CNS-resident cells during pathology analysis of markers typically absent in healthy CNS suggested that immune cell infiltration, in addition to pro-inflammatory phenotypic shifts of CNS-resident glial cells, accounts for the majority of non-CNS protein level changes in EAE, rather than passive plasma leakage.</p><p><strong>Conclusion: </strong>Together, this integrated dataset reveals coordinated multilayer molecular remodelling in neuroinflammation and refines mechanistic interpretation of biomarker origin in inflamed CNS tissue in mice.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417718","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":"Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.","authors":"Eline Bernaerts, Amber De Visscher, Sam Vanherle, Marie Rutten, Fran Prenen, Nele Berghmans, Jana Van Broeckhoven, Hanne Meers, Mirre De Bondt, Febe Boudry, Sofie Knoops, Tania Mitera, Lien De Somer, Jeroen Bogie, Patrick Matthys, Jennifer Vandooren","doi":"10.1186/s40478-026-02371-2","DOIUrl":"10.1186/s40478-026-02371-2","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdown, epitope generation, and leukocyte infiltration. In the in vivo experimental autoimmune encephalomyelitis and lysophosphatidylcholine (LPC) murine MS models, Mmp9^-/- mice exhibited delayed resolution of disease symptoms, suggesting a role for MMP-9 in remyelination. In this study, we investigated the role of MMP-9 in demyelination and remyelination, using two complementary models: LPC-induced demyelination in ex vivo brain slices and cuprizone (CPZ)-induced demyelination in vivo. In LPC-treated slices, MMP-9 deficiency impaired remyelination via microglia/macrophage-mediated mechanisms. Consistently, Mmp9^-/- mice displayed increased numbers of activated microglia/macrophages in the corpus callosum following CPZ intoxication, with modest persistence during remyelination compared to WT mice. Naïve Mmp9^-/- microglia/macrophages also showed enhanced myelin debris phagocytosis compared to WT cells. However, MMP-9 deficiency had minimal impact on demyelination or remyelination in the CPZ model. Proteomic analysis of CSF revealed differential expression of inflammatory mediators, including decreased levels of CCL2 and CXCL9, whereas CCL20 was increased in Mmp9^-/- CPZ-treated mice. Collectively, these findings indicate that MMP-9 does not directly regulate demyelination and remyelination in the CPZ-induced demyelination model, but increases microglial abundance, highlighting its indirect role in CNS demyelination.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417732","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":"Laser microdissection-based multi-omics integration unveils the pathological atlas and tumor differentiation network of adamantinomatous craniopharyngioma.","authors":"Bowen Wu, Chunming Xu, Chenxing Yang, Shenhao Xie, Suping Duan, Jiye Ye, Jinshi Zhang, Shaoyang Li, Furong Liang, Zhicheng Ye, Hai Luo, Rilege Su, Laisheng Pan, Zhizheng Liu, Shizhou Xing, Tianming Dong, Yiguang Chen, Like Chen, Suyue Zheng, Jie Wu, Tao Hong","doi":"10.1186/s40478-026-02367-y","DOIUrl":"10.1186/s40478-026-02367-y","url":null,"abstract":"<p><p>Although adamantinomatous craniopharyngioma (ACP) is a histologically benign intracranial tumor, its invasive growth pattern, characterized by finger-like protrusions, leads to a poor prognosis. In-depth analysis of the heterogeneity of the pathological structure of ACP and the development and evolution of tumor cells is crucial for expanding precision treatment strategies. However, a detailed understanding of the complex pathological structural characteristics of ACP is lacking. Here, we used laser microdissection to obtain 40 samples from 6 different pathological structures for Smart-Seq2 sequencing and conducted in-depth analysis of 6 single-nucleus RNA sequencing samples and 4 spatial transcriptome samples. We also performed comprehensive validation using 3 external single-cell databases. Through histopathological observation, multiomic analysis, and immunofluorescence staining, we resolved the single-cell expression profiles of two distinct functional subpopulations of the whorl-like cell clusters, providing insights into their potential biological roles in tumor progression. Additionally, we discovered the epithelial-mesenchymal transition (EMT) or partial EMT development direction of the stellate reticulum and different cell fates related to terminal keratinization. Moreover, we reported the presence of previously neglected cyst-wall epithelium and the constitutive epithelium within ACP. The latter was found to possess basal cell characteristics and act as a potential progenitor cell pool for tumor maintenance and evolution. Through pseudotime analysis combined with co-expression network analysis, we constructed a differentiation regulatory network based on the constitutive epithelium. Our research results complement existing knowledge and provide a comprehensive analysis of the pathological features of ACP, providing new concepts and targets for precision targeted therapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417775","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":"NR3C1 promotes group 4 medulloblastoma invasion via activating VCAN.","authors":"Jing Wang, Zichang Zhang, Han Lin, Yantao Liu, Yifei Wang, Yu Peng, Ziwen Sun, Ruichao Chai, Tao Jiang, Qing Chang","doi":"10.1186/s40478-026-02374-z","DOIUrl":"10.1186/s40478-026-02374-z","url":null,"abstract":"<p><p>Approximately 30% of group 4 medulloblastomas (G4-MBs) present with metastasis at diagnosis, yet the molecular mechanisms remain unclear. To elucidate differences of genes' expression between primary tumors of metastatic (M+) and non-metastatic (M0) G4-MB, we performed multi-omics profiling, including RNA sequencing, proteomics, single-nucleus RNA sequencing (snRNA-seq), and spatial transcriptomics on tumor samples. Integrative analyses identified VCAN, a chondroitin sulfate proteoglycan, as the most significantly up-regulated gene in primary tumors of M+ G4-MB. High expression of this gene was correlated with poor patient prognosis. Functional assays demonstrated that VCAN promotes proliferation and invasion while inhibiting apoptosis. In addition, NR3C1 was predicted as the key activator of VCAN by Single-Cell Regulatory Network Inference and Clustering (SCENIC). High-definition spatial transcriptomics revealed that NR3C1 and VCAN are highly co-expressed within the same spatial domains. Multiplex immunofluorescence confirmed the co-localization, providing spatial evidence of their regulatory interaction. ChIP-qPCR subsequently confirmed direct binding of NR3C1 to the VCAN promoter. Knockdown of NR3C1 or VCAN suppressed invasion and proliferation and induced apoptosis of the tumor cells, which were partially reversed by VCAN overexpression. Together, these findings revealed that the NR3C1-VCAN axis played a pivotal role in the metastatic progression of G4-MB, highlighting a potential therapeutic target for high-risk patients.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417744","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":"CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.","authors":"Lisa C Golden, Graham C Peet, Rebecca E Rodriguez, Nicholas J Jahahn, Gregory P Owens, Jeffrey L Bennett, Wendy B Macklin","doi":"10.1186/s40478-026-02370-3","DOIUrl":"10.1186/s40478-026-02370-3","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system. B cell depleting treatments are effective MS therapies, and while antibodies may serve as a biomarker, little is known about how they participate in MS pathology. Using a proteolipid protein 1 complex-specific (PLP1c) recombinant antibody cloned from cerebrospinal fluid plasmablasts of MS patients, we studied the development and resolution of antibody-mediated demyelinating lesions in vivo in mice. Demyelination was complement-dependent and resolved over four weeks. Because of the previously described impact of microglia on remyelination, we targeted microglia depletion with CSF1R inhibition to test their role in this model. Despite a significant reduction in total microglia following CSF1R inhibition, microglia or macrophage density was high in recovering lesions. Premyelinating oligodendrocyte populations were altered without impacting gross lesion recovery. Future work will determine if PLP1c-binding antibodies are representative of other MS-derived antibodies, and how pathogenic MS autoantibodies may contribute to the variability of MS lesion remyelination.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417723","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":"Zika virus infection induces a persistent accumulation of Alzheimer's disease-like Tau phosphorylation in adult immunocompetent mice in association with memory and social behavior impairments.","authors":"Gaetano Calcagno, Zeyni Mansuroglu, Helena Segrt, Laurine Conquet, Jose Pablo Marin-Obando, Violaine Bortolin, Fabrice de Chaumont, Luc Buée, Florence Niedergang, Caroline Manet, Marie-Christine Galas, Xavier Montagutelli, Eliette Bonnefoy","doi":"10.1186/s40478-026-02368-x","DOIUrl":"10.1186/s40478-026-02368-x","url":null,"abstract":"<p><p>Clinical and epidemiological data support the link between viral encephalitis and neurodegeneration but its causal mechanism remains mostly unknown. Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce cognitive impairments in infected adults. In this work we have analyzed the capacity of ZIKV to induce the accumulation of pathological phosphorylated Tau protein (pTau), a major driver of neurodegenerative disorders such as Alzheimer's disease, throughout the infection of adult immunocompetent mice. The capacity of ZIKV to induce pTau in vivo, was analyzed in the long term in three Collaborative Cross mouse strains displaying different responses to ZIKV. The establishment and propagation of pTau was quantified up to 60 days post-infection (dpi) in correlation with the level and localization of neuronal viral infection and of microglia activation using immunofluorescence, immunohistochemistry, wide field and confocal microscopy and gene expression analysis. Strength, coordination, memory and social behavior were evaluated before and following the establishment and progression of pTau. The role of microglia on ZIKV-induced pTau was investigated by partially depleting microglial cells using PLX3397 (PLX). ZIKV infection induced a significant accumulation of pTau starting at 15 that persisted at least until 60 dpi. At 15 dpi, pTau was observed in ZIKV-infected neurons in the CA2 and CA1 regions of the hippocampus and in non-infected cortical neurons in association with neuroinflammation and social behavior alterations. At 30 dpi, pTau progressed independently of infection and inflammation, positively correlated to PLX-susceptible Apoe gene expression in association with short-term memory defects. These results shed light on how brain viral infections, which are a major concern for public health, drive pTau accumulation and propagation in link with memory impairment and social behavior alterations laying the groundwork for potential new therapeutic treatments.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389799","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":"Challenging anatomical paradigms: unexpected supratentorial localization of posterior fossa B ependymomas identified by DNA methylation.","authors":"Pedro Piovesan Lago, Mariana Maschietto, Marllon Cindra Sant'Ana, Carlos Eduardo Ramos Fernandes, João Victor Alves de Castro, Felipe D'Almeida Costa, María Soledad Vega-Delgado, Julia Gabriela Ramos da Costa, Antonio Carlos Dos Santos, Ricardo Santos de Oliveira, Marcelo Volpon Santos, Diego Souza Lima Fonseca, Carlos Alberto Scrideli, Elvis Terci Valera","doi":"10.1186/s40478-026-02366-z","DOIUrl":"10.1186/s40478-026-02366-z","url":null,"abstract":"<p><p>Molecular subgroups of ependymomas are strongly associated with their primary anatomical compartments, namely the supratentorial region, posterior fossa and spine locations. Although it is generally accepted that posterior fossa ependymomas may arise from radial glia-like progenitor cells, the precise cellular origin of the distinct posterior fossa molecular subgroups remains to be determined. Given that DNA methylation profile strongly recapitulates developmental lineage and the cell of origin, the characterization of unexpectedly located molecular subgroups of ependymomas may provide insights into their cells of origin and potential migratory dynamics during embryogenesis and brain development. Herein, we describe two male school-aged pediatric patients with supratentorial tumors located in the third ventricle/pineal region that were classified as posterior fossa group B ependymomas based on DNA methylation profiling. To our knowledge, this represents the first reports of posterior fossa group B ependymomas identified outside the posterior fossa compartment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387180","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":"Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.","authors":"Raquel Alsina, Marta Riba, Marina Sartorio, Clara Romera, Jordi Riu, Gerard Vilaplana, Iban Aldecoa, Yaroslau Compta, Raquel Sánchez-Valle, Jaume Del Valle, Carme Pelegrí, Laura Molina-Porcel, Jordi Vilaplana","doi":"10.1186/s40478-026-02362-3","DOIUrl":"10.1186/s40478-026-02362-3","url":null,"abstract":"<p><p>The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13613785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387268","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}