Understanding Alzheimer's Disease in the Context of the Aging Brain

在大脑老化的背景下了解阿尔茨海默病

• 批准号: 9856238
• 负责人: ANA MARIA CUERVO
• 金额: $ 123.17万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9856238
• 关键词: Understanding; Alzheimer; Disease; Context; Aging

Abstract This proposal investigates the role and impact of defective maintenance of protein homeostasis (proteostasis) of the aging brain, in the development and progression of Alzheimer’s disease. Disturbances in the systems that maintain neuronal proteostasis have been observed in Alzheimer’s disease, but the extent to which loss of proteostasis in the aging brain constitutes a risk factor for development of Alzheimer’s disease remains unknown. We will focus in chaperone-mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic proteins in lysosomes. We have previously found that CMA activity decreases with age and that restoring CMA activity in old mice livers prevents their degeneration and preserves organ function. We propose that 1) the physiological decline of CMA with age increases the susceptibility of the aging brain to Alzheimer’s disease-related pathology and that 2) interventions to restore normal CMA activity in the aging brain will prevent or slow down progression of Alzheimer’s disease neurodegeneration. To test this hypothesis we intend to: 1) determine the spatiotemporal sequence of CMA changes in the aging brain to identify areas of higher susceptibility to proteotoxicity and points of “no return” to proteostasis; 2) investigate if characteristics of the Alzheimer’s disease brain are phenocopied by neuronal CMA blockage; 3) test if genetic or chemical enhancement of CMA in the aging brain increases its resistance to AD-relevant proteotoxicity and improves neuronal homeostasis and function. Significance: This study will elucidate how functional decline of CMA contributes to brain aging and if it increases Alzheimer’s disease risk in the aging brain. Our findings could help in developing new approaches to preserve old brain homeostasis and function and reduce its risk to Alzheimer’s disease neuropathology.

抽象的 该提案研究了蛋白质稳态维持缺陷的作用和影响 衰老大脑的（蛋白质稳态），阿尔茨海默氏病的发展和进展。 在阿尔茨海默病中观察到了维持神经蛋白质稳态的系统，但其程度 衰老大脑中蛋白质稳态的丧失是阿尔茨海默病发展的危险因素 我们将重点关注分子伴侣介导的自噬（CMA），一种蛋白质质量控​​制系统。 我们之前发现 CMA 介导溶酶体中胞浆蛋白的选择性降解。 活性随着年龄的增长而降低，恢复老年小鼠肝脏中的 CMA 活性可以防止其退化 保留器官功能。 我们认为1）CMA随着年龄的增长而生理性下降，增加了衰老的易感性 大脑与阿尔茨海默病相关的病理学，以及 2) 恢复正常 CMA 活性的干预措施 大脑老化将预防或减缓阿尔茨海默病神经退行性病变的进展。 为了检验这个假设，我们打算：1）确定 CMA 变化的时空序列 老化的大脑，以确定对蛋白质毒性更敏感的区域和蛋白质稳态“无法恢复”的点； 2) 研究阿尔茨海默病大脑的特征是否通过神经元 CMA 阻断进行表型复制； 3) 测试衰老大脑中 CMA 的遗传或化学增强是否会增加其对 AD 相关的抵抗力 蛋白质毒性并改善神经元稳态和功能。 意义：这项研究将阐明 CMA 功能衰退如何导致大脑衰老，以及是否会导致大脑衰老。 增加衰老大脑中患阿尔茨海默病的风险，我们的研究结果可能有助于开发新的方法来治疗。 保持旧大脑的稳态和功能，并降低其患阿尔茨海默病神经病理学的风险。