Clinical progression of tauopathies may result from transcellular propagation of pathogenic Tau seeds with the possible involvement of extracellular vesicles (EVs) as transport vectors. We established a cell model for investigating EV delivery of proteins, since the mechanism regulating EV cargo delivery to recipient cells is poorly understood. In our cell model, EVs are readily internalized and accumulate in degradative organelles (DOs). We then show for the first time that in this acidic compartment, profibrillogenic Tau delivered by EVs interacts with Tau expressed by the recipient cells and cause its accumulation by a process that involves the participation of autophagy. Thus, the degradative compartment of cells may represent the subcellular site initiating a cascade of events resulting in early hallmarks of tauopathies. These are characterized by seeded Tau accumulation, pathology-associated epitopes, DO stress, and cytotoxicity. The involvement of autophagy to this process and the relative accessibility of the degradative pathway for extracellular agents, support possible modes of intervention to slow down the progression of neurodegeneration.

中文翻译：

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细胞外囊泡中的 Tau 种子诱导细胞降解细胞器中的 Tau 积累

taupathies 的临床进展可能是由病原性 Tau 种子的跨细胞传播引起的，细胞外囊泡 (EV) 作为转运载体可能参与其中。我们建立了一个细胞模型来研究蛋白质的 EV 传递，因为调节 EV 向受体细胞传递货物的机制知之甚少。在我们的细胞模型中，EV 很容易内化并在降解细胞器 (DO) 中积累。然后我们首次证明，在这个酸性隔室中，由 EV 传递的原纤维生成 Tau 与受体细胞表达的 Tau 相互作用，并通过涉及自噬参与的过程导致其积累。因此，细胞的降解区室可能代表引发一系列事件的亚细胞位点，从而导致 tauopathies 的早期标志。这些的特点是种子 Tau 积累、病理相关表位、DO 应激和细胞毒性。自噬参与该过程以及细胞外物质降解途径的相对可及性，支持可能的干预模式以减缓神经变性的进展。