Exosome Mediated Alterations in Cellular Metabolism in the Pathogenesis and Progression of Alzheimer's Disease

7.项目概要/摘要 外泌体分泌和含量的改变与阿尔茨海默病（AD）有关。这些 纳米囊泡在循环中是丰富的，并且正在被检查为有希望的基于血液的生物标志物， 疾病重要的是，来自AD患者和动物模型的外泌体已显示携带 病原性货物，并可能有助于神经元功能障碍的传播。我们的初步数据显示 新的证据表明，早期AD病理生理学的关键特征，如线粒体功能障碍， 改变的细胞代谢，可以由源自AD患者的外来体介导。拟定的研究将 测试循环外泌体介导与以下相关的细胞代谢的系统性变化的假设： AD的早期阶段，并有助于AD病理学在疾病的长期进展中的传播。 该提案的主要目标是：1）表征总的、神经元衍生的和星形胶质细胞衍生的外泌体 使用整合组学分析，在AD的各个阶段和疾病的3年进展中;以及2） 研究外泌体影响细胞代谢、AD病理和认知能力下降的机制 使用互补的体外、离体和体内方法。 这项拟议的研究利用了一个独特而及时的机会，利用血浆样本， 正在进行的由美国国立卫生研究院资助的对维克森林阿尔茨海默病中心临床核心参与者的研究。与 样本收集、关键临床措施和人类生物能量分析的费用， 资金，我们有一个宝贵的机会来推进我们对外来体介导的细胞间 交流参与AD病理生理学的发病和传播。这项研究的结果将提供 对AD病理学介质的新机制见解，并可能转移AD预防的重点， 治疗包括靶向外泌体介导的细胞间信号传导的有害作用的策略， 全身性生物能量下降本研究的强大框架将支持未来的研究工作， 推进新的体外和体内实验方法，并通过产生全面的外泌体， 与正在进行的AD纵向队列研究相关的储存库和数据库。

7. Project Summary/Abstract Alterations in exosome secretion and content have been linked to Alzheimer's disease (AD). These nanovesicles are abundant in circulation and are being examined as promising blood-based biomarkers of disease. Importantly, exosomes derived from AD patients and animal models have been shown to carry pathogenic cargo and can contribute to the spread of neuronal dysfunction. Our preliminary data provide striking new evidence that key features of early AD pathophysiology, such as mitochondrial dysfunction and altered cellular metabolism, can be mediated by exosomes derived from AD patients. The proposed study will test the hypothesis that circulating exosomes mediate systemic changes in cellular metabolism associated with early stages of AD and contribute to the spread of AD pathology over the long-term progression of disease. The primary goals of this proposal are: 1) to characterize total, neuron-derived, and astrocyte-derive exosomes across stages of AD and over the 3 year progression of disease using integrated omics analysis; and 2) to examine the mechanisms by which exosomes affect cellular metabolism, AD pathology, and cognitive decline using complementary in vitro, ex vivo, and in vivo approaches. The proposed study capitalizes on a unique and timely opportunity to utilize plasma samples from an ongoing NIA-funded study of participants in the Wake Forest Alzheimer' Disease Center Clinical Core. With the costs for sample collections, key clinical measures, and human bioenergetic profiling covered by existing funding, we have a valuable opportunity to advance our understanding of how exosome-mediated intercellular communication is involved in the onset and spread of AD pathophysiology. The results of this study will provide new mechanistic insights into mediators of AD pathology and could shift the focus of AD prevention and therapy to include strategies targeting the detrimental effects of exosome mediated intercellular signaling and systemic bioenergetic decline. The robust framework of this study will support future research efforts by advancing novel in vitro and in vivo experimental approaches, and by generating a comprehensive exosome repository and database linked to an ongoing longitudinal cohort study of AD.