Enrichment of neurally derived extracellular vesicles of several cell‐types from plasma for protein quantification longitudinally in living patients with Alzheimer’s disease has permitted the development of a tentative temporal framework of initiating events, progression mechanisms, and amplification processes. Interactions of beta‐amyloid peptides with an elevated level of their normal prion protein dendritic receptor and of phospho‐tau species with their synaptogyrin‐3 synaptic vesicle receptor replace excessive production and accumulation of neuropathic proteins as the major initiating events. Synaptic dysfunction and microvascular angiopathy are confirmed as early progression mechanisms of decreased neuronal network connectivity, hypoxia, altered blood‐brain barrier, and neurocellular degeneration. Neurally derived extracellular vesicle protein abnormalities also reveal a range of later amplification processes that encompasses insulin resistance, lysosomal defects, decreased survival factors, increased reactive oxygen species, and excessive neuroinflammation. New potential therapeutic targets also are suggested as well as the likely timing of their pathogenic engagement.

中文翻译：

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阿尔茨海默病的先进药物：血浆神经外泌体平台

从血浆中富集神经来源的几种细胞类型的细胞外囊泡，用于阿尔茨海默病活着的患者的蛋白质纵向定量，这已经允许建立一个关于起始事件、进展机制和放大过程的暂定时间框架。β-淀粉样肽与其正常朊病毒蛋白树突受体水平升高以及磷酸-tau 物质与其突触 3 突触囊泡受体的相互作用取代了神经病蛋白的过度产生和积累，成为主要的起始事件。突触功能障碍和微血管病变被证实是神经元网络连接减少、缺氧、血脑屏障改变和神经细胞变性的早期进展机制。神经来源的细胞外囊泡蛋白异常还揭示了一系列后期扩增过程，包括胰岛素抵抗、溶酶体缺陷、存活因子降低、活性氧增加和过度神经炎症。还建议了新的潜在治疗靶点以及它们致病作用的可能时间。