Fowler Stephanie L, Behr Tiana S, Turkes Emir, O'Brien Darragh P, Cauhy Paula Maglio, Rawlinson Isadora, Edmonds Marisa, Foiani Martha S, Schaler Ari, Crowley Gerard, Bez Sumi, Ficulle Elena, Tsefou Eliona, Fischer Roman, Geary Beth, Gaur Pallavi, Miller Chelsea, D'Acunzo Pasquale, Levy Efrat, Duff Karen E, Ryskeldi-Falcon Benjamin
UK Dementia Research Institute at University College London, London, UK.
Oxford-GSK Institute of Molecular and Computational Medicine, University of Oxford, Oxford, UK.
Nat Neurosci. 2025 Jan;28(1):40-48. doi: 10.1038/s41593-024-01801-5. Epub 2024 Nov 21.
The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). Assembled tau associates with extracellular vesicles (EVs) in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from individuals with AD. We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
tau蛋白在神经元中的异常组装是包括阿尔茨海默病（AD）在内的多种神经退行性疾病的病理标志。在患有AD的个体的中枢神经系统中，组装好的tau与细胞外囊泡（EVs）相关联，这与其清除和朊病毒样传播有关。然而，组装好的tau种类和EVs的身份，以及它们如何关联，尚不清楚。在这里，我们结合了定量质谱、冷冻电子断层扫描和单颗粒冷冻电子显微镜来研究来自患有AD的个体的脑EVs。我们发现tau细丝主要由截短的tau组成，这些细丝被包裹在富含内溶酶体蛋白的EVs中。我们观察到多种细丝相互作用，包括与将细丝拴在EV限制膜上的分子的相互作用，这表明存在选择性包装。我们的发现将指导对EV介导的组装好的tau分泌的分子机制的研究，并为将与EV相关的tau作为AD的潜在治疗和生物标志物策略的靶点提供信息。
