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

外泌体介导的阿尔茨海默病发病机制和进展中细胞代谢的改变

• 批准号: 9923988
• 负责人: ANTHONY J MOLINA
• 金额: $ 72.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923988
• 关键词: Acute; Adult; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid deposition; Animal Model; Apolipoprotein E; Astrocytes; Bioenergetics; Bioinformatics; Biology; Biometry; Blood Circulation; Brain; Brain Diseases; Brain imaging; Cells; Clinical; Cognition; Communities; Data; Databases; Development; Disease; Disease Progression; Early Diagnosis; Foundations; Functional disorder; Funding; Future; Genotype; Goals; Human; Impaired cognition; In Vitro; Link; Longitudinal cohort study; Measures; Mediating; Mediator of activation protein; Metabolic dysfunction; Metabolism; Microglia; Mitochondria; Mus; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Peripheral; Plasma; Play; Positron-Emission Tomography; Prevention therapy; Proteins; Proteomics; Quality Control; Research; Research Personnel; Resolution; Sampling; Signal Transduction; Slice; Testing; Time; Tissues; Work; blood-based biomarker; cognitive performance; cognitive testing; cohort; cost; design; disease diagnosis; exosome; follow-up; forest; glucose metabolism; high throughput analysis; in vivo; insight; intercellular communication; intravenous injection; metabolic profile; metabolomics; mild cognitive impairment; mitochondrial dysfunction; monocyte; mouse model; multiple omics; nanovesicle; novel; pre-clinical; repository; sample collection; synaptic function; tau Proteins; tau-1; transcriptome sequencing

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.

7.项目摘要/摘要 外切体分泌和含量的改变与阿尔茨海默病(AD)有关。这些 纳米囊泡在血液循环中含量丰富，正被视为有希望的血液生物标志物。 疾病。重要的是，来自AD患者和动物模型的外切体已被证明携带 致病的货物，可促进神经功能障碍的传播。我们的初步数据提供了 惊人的新证据表明，早期AD的主要病理生理学特征，如线粒体功能障碍和 细胞代谢改变，可由AD患者来源的外切体介导。拟议的研究将 检验循环外切体介导与以下相关的细胞代谢系统变化的假说 阿尔茨海默病是阿尔茨海默病的早期阶段，有助于在疾病的长期发展中传播阿尔茨海默病的病理。 这项提议的主要目标是：1)表征总的、神经元来源的和星形胶质细胞来源的外切体 使用综合组学分析跨越AD各阶段和超过3年的疾病进展；以及2) 研究外切体影响细胞新陈代谢、AD病理和认知功能衰退的机制 采用体外、体外和体内互补的方法。 这项拟议的研究利用了一个独特和及时的机会来利用来自 NIA正在对维克森林阿尔茨海默病中心临床核心的参与者进行研究。与 样本采集、关键临床措施和人体生物能量分析的成本由现有的 资金，我们有一个宝贵的机会来促进我们对外切体介导的细胞间 沟通参与了AD病理生理的发生和发展。这项研究的结果将提供 对AD病理介质的新的机械性见解，并可能转移AD预防和治疗的重点 治疗包括针对外切体介导的细胞间信号转导和 全身性生物能量衰退。这项研究的强大框架将通过以下方式支持未来的研究工作 发展新的体外和体内实验方法，并通过产生一个全面的外切体 与正在进行的AD纵向队列研究相关联的存储库和数据库。