BACKGROUND The contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer's disease (AD) remain poorly understood. METHODS Here, we investigated the role(s) of brain EV in the progressive course of AD through unbiased proteome-wide analyses of temporal lobe-derived EV and proteome-label quantitation of complementary remaining brain portions. Furthermore, relevant proteins identified were further screened by multiple reaction monitoring. RESULTS Our data indicate that EV biogenesis was altered during preclinical AD with the genesis of a specific population of EV containing MHC class-type markers. The significant presence of the prion protein PrP was also manifested in these brain vesicles during preclinical AD. Similarly, sequestration of amyloid protein APP in brain EV coincided with the observed PrP patterns. In contrast, active incorporation of the mitophagy protein GABARAP in these brain vesicles was disrupted as AD progressed. Likewise, disrupted incorporation of LAMP1 in brain EV was evident from the initial manifestation of AD clinical symptoms, although the levels of the protein remained significantly upregulated in the temporal lobe of diseased brains. CONCLUSIONS Our findings indicate that impaired autophagy in preclinical AD coincides with the appearance of proinflammatory and neuropathological features in brain extracellular vesicles, facts that moderately remain throughout the entire AD progression. Thus, these data highlight the significance of brain EV in the establishment of AD neuropathology and represent a further leap toward therapeutic interventions with these vesicles in human dementias.

中文翻译：

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阿尔茨海默病的进展以脑细胞外囊泡分子谱和生物发生的改变为特征。


背景脑细胞间通讯机制，特别是细胞外囊泡（EV）对阿尔茨海默病（AD）进展的贡献仍然知之甚少。方法在这里，我们通过对颞叶来源的 EV 进行无偏蛋白质组范围分析以及对互补的剩余大脑部分进行蛋白质组标记定量，研究了脑 EV 在 AD 进展过程中的作用。此外，通过多重反应监测进一步筛选鉴定出的相关蛋白。结果我们的数据表明，在临床前 AD 期间，随着含有 MHC 类标记的特定 EV 群体的发生，EV 生物发生发生了改变。在临床前 AD 期间，这些脑泡中也显示出朊病毒蛋白 PrP 的显着存在。同样，大脑 EV 中淀粉样蛋白 APP 的隔离与观察到的 PrP 模式一致。相比之下，随着 AD 的进展，这些脑泡中线粒体自噬蛋白 GABARAP 的主动掺入被破坏。同样，从 AD 临床症状的最初表现来看，大脑 EV 中 LAMP1 的整合被破坏，尽管该蛋白的水平在患病大脑的颞叶中仍然显着上调。结论 我们的研究结果表明，临床前 AD 中自噬受损与脑细胞外囊泡中促炎和神经病理学特征的出现相一致，这些事实在整个 AD 进展过程中适度保留。因此，这些数据强调了脑 EV 在 AD 神经病理学建立中的重要性，并代表着利用这些囊泡对人类痴呆症进行治疗干预的进一步飞跃。