Skeletal muscle extracellular vesicle signaling in Alzheimer's Disease prevention

摘要 阿尔茨海默病（AD）是一种以蛋白质的存在为特征的破坏性疾病， 在大脑内聚集，与突触神经丧失和进行性认知缺陷密切相关。一 生活方式干预，如运动，可以改善AD患者的认知功能。虽然机制 介导这种变化的可能是多因素的，我们的建议调查了一种新的细胞对细胞的潜力。 通过转移细胞外囊泡（EV;外来体和微囊泡）来介导的信号传导机制 神经细胞的变化。我们的初步数据显示，有氧运动既可以增加 血清中EV的含量及其热休克蛋白（HSP）的含量。此外，我们证明，电动汽车 升高的HSP可抑制神经元细胞内的蛋白聚集。我们提供了额外的证据 提示EV清除使用自噬体途径。我们的中心假设是运动 诱导的EV可以阻碍通常与AD相关的蛋白质聚集。在本提案中，我们将 在两个独立的具体目标中进行测试。目的1将评估AD患者的运动是否调节EV 内容、数量和功能（即，阻断蛋白质聚集的能力）。目标2将评估分子 运动诱发的电动汽车及其相关的HSP可能起作用的基础。在后 目的是检测自噬体通路是否参与了β淀粉样肽（Aβ）的清除 含有蛋白质聚集体。该建议代表了研究AD的创新方法， 有可能深入了解运动如何改善AD结局，并最终可能提供新的 治疗方法。

ABSTRACT Alzheimer's Disease (AD) represents a devastating disease characterized by the presence of protein aggregates within the brain that are closely linked to synaptic nerve loss and progressive cognitive deficits. A lifestyle intervention, such as exercise, can improve cognitive function in AD patients. While the mechanisms that mediate this change are likely multifactorial, our proposal investigates the potential for a novel cell-to-cell signaling mechanism via transfer of extracellular vesicles (EV; exosomes and microvesicles) to mediate changes in the neuronal cells. Our preliminary data show that aerobic exercise can both increase the number of EVs in serum as well as their content of heat shock proteins (HSP). Moreover, we demonstrate that EVs with elevated HSP can inhibit protein aggregation within neuronal cells. We provide additional evidence suggesting this EV clearance uses an autophagosomal pathway. Our central hypothesis is exercise induced EVs can impede the protein aggregation typically associated with AD. In this proposal we will test this in two independent specific aims. Aim 1 will assess whether exercise of AD patients modulates EV content, numbers and function (i.e., ability to block protein aggregation). Aim 2 will assess the molecular underpinning through which exercise- induced EVs and their associated HSPs might be working. In this latter aim, we will test whether the autophagosomal pathway is involved in the removal of amyloid-β-peptide (Aβ) containing protein aggregates. This proposal represents an innovative approach to study AD, and has the potential to provide insight into how exercise can improve AD outcomes and ultimately may provide novel therapeutic approaches.