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多种神经退行性疾病的病理标志，包括阿尔茨海默病 （AD）。组装的 tau 与 AD 个体中枢神经系统中的细胞外囊泡 （EV） 相关，这与其清除和朊病毒样传播有关。然而，组装的 tau 物种和 EV 的身份以及它们如何结合尚不清楚。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 AD 患者的脑 EV。我们发现 tau 丝主要由截短的 tau 组成，这些 tau 被封闭在富含溶酶体内蛋白的 EV 中。我们观察到多种细丝相互作用，包括与将细丝拴在 EV 限制膜上的分子相互作用，表明选择性包装。我们的研究结果将指导对 EV 介导的组装 tau 分泌的分子机制的研究，并为靶向 EV 相关 tau 作为 AD 的潜在治疗和生物标志物策略提供信息。