The role of activity induced exosome signaling in synaptic pathology of Alzheimer's Disease

摘要 突触功能障碍是阿尔茨海默病（AD）的核心病理标志。中的减损 突触是神经元回路活动变化的基础，最终导致AD认知受损。 尽管如此，我们目前对AD中突触是如何以及为什么发生改变的了解还不完全 病理如果我们能进一步了解导致突触功能障碍的潜在机制 在AD中，这将是对AD的全面理解的重大进步。新近证据已表明 致病性淀粉样蛋白β和tau蛋白在细胞外囊泡和外泌体中富集;但这些囊泡如何 对疾病进展的贡献，特别是它们如何影响突触功能，仍然是未知的。初步 研究中，我们提供的证据表明，突触NMDA受体的激活触发神经元中的外泌体释放， 这个过程调节了许多突触蛋白的水平。重要的是，分析这些复杂的 使用多种生物信息学策略的数据集，突出了关键的蛋白质-蛋白质相互作用网络， 受外泌体调节，包括AMPA受体、淀粉样前体蛋白（APP）和tau的存在。 对来自刺激神经元的纯化外泌体的蛋白质组学分析显示存在几种蛋白质 已知会导致神经退行性变，这表明这个过程可能在神经退行性变的传播中起着重要作用。 病理抑制WT神经元中的外泌体合成消除了突触增强，证明了神经元的突触增强。 以前未知的外泌体信号传导功能。对来自多个人的脑的纯化的外来体的分析 AD样病理的小鼠模型显示APP和淀粉样β肽的富集， 外泌体蛋白质货物的改变。基于这些证据，我们假设正常的外泌体信号传导 被AD病理学劫持，导致已知在该疾病中普遍存在的突触功能障碍。我们 提出，活动诱导的外泌体，通常支持突触加强，被淹没 致病分子的异常富集，导致突触破坏，特别是受损 突触强化我们计划通过结合正交技术和学科来检验这一假设 包括突触功能的电生理学测量，无偏蛋白质组学方法， 外泌体释放动力学的成像。这项拟议中的研究有可能改变我们对 活动诱导的外泌体信号传导如何改变可能导致突触功能障碍和AD的扩散， 比如病理学

ABSTRACT Synaptic dysfunction represents a core pathological hallmark of Alzheimer's disease (AD). Impairments in synapses underlie changes in the activity of neuronal circuits, which ultimately drive impaired cognition in AD. Despite this, we currently have an incomplete understanding of how and why synapses are altered in AD pathology. If we could advance our understanding of the underlying mechanisms that cause synaptic dysfunction in AD, it would be a significant advancement in the overall understanding of AD. Recent evidence has suggested that pathogenic amyloid beta and tau are enriched in extracellular vesicles and exosomes; but how these vesicles contribute to disease progression, particularly how they affect synaptic function, is still unknown. In preliminary studies, we provide evidence that activation of synaptic NMDA receptors triggers exosome release in neurons, and that this process regulates the level of many synaptic proteins. Importantly, an analysis of these complex datasets using multiple bioinformatic strategies, highlighted key protein-protein interaction networks that are regulated by exosomes including the presence of AMPA receptors, amyloid precursor protein (APP), and tau. Proteomic analysis of purified exosomes from stimulated neurons revealed the presence of several proteins known to cause neurodegeneration, and it suggests that this process may have a major role in the spreading of pathology. Inhibition of exosome synthesis in WT neurons eliminated synaptic potentiation demonstrating a previously unknown function of exosome signaling. Analysis of purified exosomes from the brains of multiple mouse models with AD-like pathology demonstrated an enrichment of APP and amyloid beta peptide as well as an alteration of exosome protein cargos. Based on this evidence, we hypothesize that normal exosome signaling is hijacked by AD pathology contributing to the synaptic dysfunction known to be prevalent in the disease. We propose that activity-induced exosomes, which normally support synaptic strengthening, are overwhelmed by aberrant enrichment of pathogenic molecules which results in disrupted synapses, in particular, impaired synaptic strengthening. We plan to test this hypothesis by combining orthogonal techniques and disciplines including electrophysiological measurement of synaptic function, non-biased proteomic approaches, and imaging of exosome release dynamics. The proposed research has the potential to transform our understanding of how altered activity-induced exosome signaling may contribute to synaptic dysfunction and spreading of AD- like pathology.