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.

抽象的阿尔茨海默氏病（AD）代表了一种毁灭性疾病，其特征是存在蛋白质大脑中与突触神经损失和进行性认知缺陷密切相关的骨料。一个生活方式干预（例如运动）可以改善AD患者的认知功能。而机制调解这种变化的可能是多因素，我们的建议研究了新型细胞到细胞的潜力信号传导机制通过细胞外蔬菜（EV；外泌体和微覆物）转移以介导神经元细胞的变化。我们的初步数据表明，有氧运动都可以增加数量血清中的电动汽车及其热激蛋白（HSP）的含量。而且，我们证明了电动汽车 HSP升高可以抑制神经元细胞内的蛋白质聚集。我们提供其他证据建议这种EV间隙使用自噬体途径。我们的中心假设是锻炼诱导的电动汽车会阻碍通常与AD相关的蛋白质聚集。在这个建议中，我们将在两个独立的特定目标中测试这一点。 AIM 1将评估AD患者的行使是否调节EV 内容，数字和功能（即阻断蛋白质聚集的能力）。 AIM 2将评估分子锻炼引起的电动汽车及其相关的HSP可能起作用的基础。稍后目的，我们将测试自噬体途径是否参与去除淀粉样蛋白β-肽（Aβ）包含蛋白质聚集体。该建议代表了研究广告的创新方法，并具有潜力可以洞悉运动如何改善广告结果，并最终提供新颖治疗方法。