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

基本信息

批准号：
10390460
负责人：
ANTHONY J MOLINA
金额：
$ 69.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390460
关键词：
Acute Adult Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-42 Amyloid deposition Animal Model Apolipoprotein E Astrocytes Bioenergetics Bioinformatics Biology Biometry Blood Circulation Brain 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 Magnetic Resonance Imaging Measures Mediating Mediator of activation protein Metabolic 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 clinical center cognitive performance cognitive testing cohort cost design exosome follow-up forest glucose metabolism high throughput analysis in vivo insight intercellular communication intravenous injection 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

项目摘要

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. 项目总结/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系统中含量丰富，正在作为有希望的基于血液的生物标志物进行检查疾病。重要的是，来自 AD 患者和动物模型的外泌体已被证明携带致病货物并可能导致神经元功能障碍的传播。我们的初步数据提供惊人的新证据表明早期 AD 病理生理学的关键特征，例如线粒体功能障碍和细胞代谢的改变可以由来自 AD 患者的外泌体介导。拟议的研究将检验循环外泌体介导与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）表征总外泌体、神经元衍生外泌体和星形胶质细胞衍生外泌体使用综合组学分析了解 AD 的各个阶段以及 3 年的疾病进展情况； 2) 至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。拟议的研究利用了一个独特而及时的机会，利用来自 NIA 资助的正在进行的针对维克森林阿尔茨海默病中心临床核心参与者的研究。随着现有的样本采集、关键临床测量和人体生物能量分析的成本资金，我们有一个宝贵的机会来加深我们对外泌体介导的细胞间质的理解沟通参与 AD 病理生理学的发生和传播。这项研究的结果将提供对 AD 病理学介质的新机制见解，可能会改变 AD 预防和治疗的重点治疗包括针对外泌体介导的细胞间信号传导的有害影响的策略和全身生物能下降。本研究的稳健框架将支持未来的研究工作推进新颖的体外和体内实验方法，并通过生成全面的外泌体与正在进行的 AD 纵向队列研究相关的存储库和数据库。