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Skeletal muscle extracellular vesicle signaling in Alzheimer's Disease prevention

骨骼肌细胞外囊泡信号传导在阿尔茨海默病预防中的作用

基本信息

批准号：
9917535
负责人：
LANE K. CHRISTENSON
金额：
$ 42.08万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917535
关键词：
Abeta clearance Acute Address Aerobic Exercise Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid beta-Protein Amyloid beta-Protein Precursor Automobile Driving Behavior Biological Assay Brain Cell physiology Cells Chronic Cognitive deficits Data Deposition Development Disease Disease Outcome Disease Progression Excision Exercise Extracellular Space Future Generations Heat shock proteins Human In Vitro Intervention Investigation Link Mediating Memory Microglia Molecular Muscle Nerve Nerve Regeneration Neurofibrillary Tangles Neurons Pathologic Pathway interactions Patients Performance Phospholipids Proteins Resources Risk Role Sampling Senile Plaques Serum Signal Transduction Skeletal Muscle Synapses Testing Toxic effect Travel Vesicle brain tissue cell behavior cognitive function exosome extracellular vesicles improved in vivo innovation insight lifestyle intervention microvesicles non-demented novel novel therapeutic intervention novel therapeutics overexpression prevent protein aggregation social synaptic function

项目摘要

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.

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。