英国MRC分子生物学实验室Benjamin Ryskeldi-Falcon等研究人员合作发现，阿尔茨海默病中Tau丝被固定在大脑的细胞外囊泡内。2024年11月21日，国际知名学术期刊《自然—神经科学》在线发表了这一成果。

研究人员表示，Tau蛋白在神经元中的异常聚集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特征。在患有AD的个体中，聚集的Tau与中枢神经系统的细胞外囊泡（EV）相关联，这与其清除及类似朊病毒的传播有关。然而，聚集的Tau种类和EVs的特性以及它们之间的关联方式尚不清楚。

研究人员结合定量质谱、冷冻电子断层扫描及单颗粒冷冻电镜技术，研究了来自AD患者的大脑EV。研究人员发现，Tau丝主要由截短的Tau组成，被封闭在富含内吞-溶酶体蛋白的EV内。研究人员观察到多种丝状相互作用，包括与将丝固定在EV限制膜上的分子的相互作用，表明存在选择性包装。

这些发现将为研究EV介导的Tau聚集物分泌的分子机制提供指导，并为以EV相关Tau为靶点的AD治疗和生物标志物策略提供参考。

附：英文原文

Title: Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease

Author: Fowler, Stephanie L., Behr, Tiana S., Turkes, Emir, OBrien, 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, DAcunzo, Pasquale, Levy, Efrat, Duff, Karen E., Ryskeldi-Falcon, Benjamin

Issue&Volume: 2024-11-21

Abstract: 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.

DOI: 10.1038/s41593-024-01801-5

Source: https://www.nature.com/articles/s41593-024-01801-5