Molecular Neurodegeneration最新文献

{"title":"Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia","authors":"Yanaika S. Hok-A-Hin, Lisa Vermunt, Carel F.W. Peeters, Emma L. van der Ende, Sterre C.M. de Boer, Lieke H. Meeter, Julie de Houwer, Harro Seelaar, John C. van Swieten, William T. Hu, Alberto Lleó, Daniel Alcolea, Sebastiaan Engelborghs, Anne Sieben, Alice Chen-Plotkin, David J. Irwin, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Charlotte E. Teunissen, Marta del Campo","doi":"10.1186/s13024-025-00882-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00882-5","url":null,"abstract":"Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"24 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.","authors":"Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass","doi":"10.1186/s13024-025-00878-1","DOIUrl":"10.1186/s13024-025-00878-1","url":null,"abstract":"<p><p>Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"92"},"PeriodicalIF":17.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Clinical progression and genetic pathways in body-first and brain-first Parkinson's disease.","authors":"Massimiliano Passaretti, Daniel Veréb, Mite Mijalkov, Yu-Wei Chang, Hang Zhao, Blanca Zufiria-Gerbolés, Jiawei Sun, Giovanni Volpe, Natalia Rivera, Matteo Bologna, Joana B Pereira","doi":"10.1186/s13024-025-00885-2","DOIUrl":"10.1186/s13024-025-00885-2","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"91"},"PeriodicalIF":17.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein","authors":"Jingfeng Liang, Rongzhen Li, Garry Wong, Xiaobing Huang","doi":"10.1186/s13024-025-00879-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00879-0","url":null,"abstract":"Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"37 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2 kinase activity regulates Parkinson’s disease-relevant lipids at the lysosome","authors":"Michael T. Maloney, Xiang Wang, Rajarshi Ghosh, Shan V. Andrews, Romeo Maciuca, Shababa T. Masoud, Maayan Agam, Richard M. Caprioli, Giuseppe Astarita, Vitaliy V. Bondar, John Chen, Chi-Lu Chiu, Sonnet S. Davis, Audrey Cheuk-Nga Ho, Hoang N. Nguyen, Nicholas E. Propson, Michelle L. Reyzer, Oliver B. Davis, Matthew C. Deen, Sha Zhu, Gilbert Di Paolo, David J. Vocadlo, Anthony A Estrada, Javier de Vicente, Joseph W. Lewcock, Annie Arguello, Jung H. Suh, Sarah Huntwork-Rodriguez, Anastasia G. Henry","doi":"10.1186/s13024-025-00880-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00880-7","url":null,"abstract":"Pathogenic variants in LRRK2 lead to increased kinase activity, and LRRK2 kinase inhibition is being explored in clinical studies as a therapeutic approach for Parkinson’s Disease (PD). LRRK2 inhibitors reduce urine levels of bis(monoacylglycerol)phosphate (BMP), a key endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in preclinical models and clinical subjects. However, how LRRK2 regulates BMP and its significance with respect to lysosomal dysfunction in PD are poorly defined. Using a combination of genetic and pharmacological approaches to modulate LRRK2 kinase activity, we explored the mechanisms by which LRRK2 can regulate the levels of BMP and PD-relevant GSLs across cellular models, including iPSC-derived microglia, and in tissues and biofluids from mice using mass spectrometry. The impact of LRRK2 activity on various aspects of lysosomal function, including endolysosomal GCase activity, was assessed using live-cell imaging and lysosomal immunoprecipitation. We employed imaging mass-spectrometry and FACS-based methods to specifically examine how LRRK2 modulates BMP and GSL levels across different cell types and regions of the brain. To confirm the relevance of our findings to disease, we measured lysosomal biomarkers in urine and cerebrospinal fluid (CSF) from human subjects carrying variants in LRRK2 associated with PD risk and from subjects dosed with a LRRK2 kinase inhibitor. Our data demonstrate that LRRK2 can employ distinct mechanisms to control intracellular BMP levels and modulate lysosomal homeostasis depending on the tissue examined. We show that LRRK2 deletion or inhibition lowers urine BMP levels by reducing the secretion of BMP-containing vesicles from kidney into urine. In other cell types such as microglia, LRRK2-mediated inhibition of β-glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism, leads to lysosomal GSL accumulation and increases BMP levels as a compensatory response to restore lysosomal homeostasis. LRRK2 inhibition normalizes lysosomal function and reduces GSL levels in preclinical models and CSF from LRRK2-PD patients. Our study highlights the therapeutic potential of LRRK2 kinase inhibition to improve PD-associated lysosomal dysfunction and supports the utility of GSLs as CSF-based biomarkers of LRRK2 activity. This work includes results from the following phase 1b study in PD patients: ClinicalTrials.gov ID: NCT03710707; https://clinicaltrials.gov/study/NCT03710707?intr=dnl201&rank=2 . The date of registration was 10/18/2018.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144792628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A manifesto for Alzheimer’s disease drug discovery in the era of disease-modifying therapies","authors":"Heike Hering, Thierry Bussiere, Chia-Chen Liu, Kelly E. Glajch, Andreas Weihofen, Jane Grogan, Dominic M. Walsh","doi":"10.1186/s13024-025-00872-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00872-7","url":null,"abstract":"After decades of disappointment, three disease-modifying therapies for Alzheimer’s disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5– implications for dementia with lewy bodies","authors":"Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Diana L Price, Christina Patrick, Paula Desplats, Eliezer Masliah","doi":"10.1186/s13024-025-00881-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00881-6","url":null,"abstract":"<p><b>Retraction Note</b></p><p>The Editorial team has retracted this article.</p><p>After publication, concerns were raised regarding some of the data presented in the figures. Specifically:</p><ul>\u0000<li>\u0000<p>Panels <i>Non tg</i> and <i>APP tg</i> in the second row of Fig. 5A appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non tg</i> in the third rows of Fig. 6B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the first row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>Non-tg</i> in the second rows of Fig. 7B and D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Panels <i>APP tg</i> and <i>alpha-syn tg</i> in the third row of Fig. 7D appear to overlap;</p>\u0000</li>\u0000<li>\u0000<p>Some blots in Fig. 9c appear to have similar bands between the two LV-control groups (vehicle and Aβ1–42).</p>\u0000</li>\u0000</ul><p>The authors have stated that these errors occurred during figure preparation. However, due to the number of concerns, the Editors-in-Chief no longer have confidence in the presented data.</p><p>Cassia R Overk and Eliezer Masliah disagree with this retraction. The other authors have not responded to any correspondence from the editor or publisher about this retraction.</p><h3>Authors and Affiliations</h3><ol><li><p>Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA</p><p>Cassia R Overk, Anna Cartier, Gideon Shaked, Edward Rockenstein, Kiren Ubhi, Brian Spencer, Christina Patrick, Paula Desplats &amp; Eliezer Masliah</p></li><li><p>Neuropore Therapies, Inc, San Diego, CA, 92121, USA</p><p>Diana L Price</p></li><li><p>Department of Pathology, University of California, San Diego, La Jolla, CA, USA</p><p>Eliezer Masliah</p></li></ol><span>Authors</span><ol><li><span>Cassia R Overk</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Anna Cartier</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Gideon Shaked</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Edward Rockenstein</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Kiren Ubhi</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Brian Spencer</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Diana L Price</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Christina Patrick</span>View author publications<p><span>Search author on:</span><span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Paula Desplats</span>View author publications<p><span>Search author on:</span><span>PubMed<span> <","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144778200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycerophospholipids in ALS: insights into disease mechanisms and clinical implication","authors":"Thibaut Burg, Ludo Van Den Bosch","doi":"10.1186/s13024-025-00876-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00876-3","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting the adult motor system, with no effective treatments available. Despite extensive research efforts, the exact pathological cascade leading to progressive motor neuron degeneration remains elusive. Recent evidence highlights significant modifications in lipid metabolism during ALS progression, even before the onset of motor symptoms. Glycerophospholipids, the primary components of cellular membranes, are frequently altered in ALS patients and models. These lipids not only play a structural role in membranes, but also contribute to cellular metabolism, signaling pathways, and cell type-specific processes such as neuronal transmission and muscle contraction. In this review, we discuss glycerophospholipid physiological functions in the motor system and review recent studies demonstrating their alterations and the possible underlying pathological mechanisms in ALS. Furthermore, we discuss challenges emerging from studying lipid alterations in neurodegeneration and evaluate the therapeutic potential of glycerophospholipids.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"14 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases","authors":"Hideyuki Takahashi, Stephen M. Strittmatter","doi":"10.1186/s13024-025-00873-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00873-6","url":null,"abstract":"Although different neurodegenerative diseases are defined by distinct pathological proteins, they share many common features including protein aggregation. Despite this commonality, most current therapeutic approaches in the field, such as anti-aggregate antibodies, are focused on individual diseases or single neuropathologies with only limited success. The endolysosomal proteins progranulin and TMEM106B were both initially associated with frontotemporal lobar degeneration but have subsequently also been linked to other neurodegenerative diseases. Thus, these proteins are predicted to participate in common pathogenic pathways shared across various neurodegenerative diseases. Importantly, recent discoveries of TMEM106B amyloid fibrils in varied neurodegenerative diseases and glycosphingolipid regulation by progranulin and TMEM106B further support their central roles in cross-disease neurodegenerative mechanisms. This review summarizes recent advances in progranulin and TMEM106B function within the endolysosomal system and neurodegenerative diseases. It describes preclinical models and therapeutic approaches for progranulin- and TMEM106B-associated diseases. We also discuss future direction leading to novel alternative therapies targeting shared mechanisms in neurodegenerative diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer’s disease","authors":"Pingao Zhang, Chenghuan Song, Jiyun Shi, Zijie Wei, Jing Wang, Wanying Huang, Rui Zhang, Jintao Wang, Xiaoli Yang, Gang Wang, Xiaoling Gao, Yongfang Zhang, Hongzhuan Chen, Hao Wang","doi":"10.1186/s13024-025-00875-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00875-4","url":null,"abstract":"Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}