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

摘要 这项建议调查了有缺陷的蛋白质稳态维持的作用和影响 (蛋白质平衡)衰老的大脑，在阿尔茨海默病的发展和进展中。骚乱发生在 在阿尔茨海默病中观察到了维持神经元蛋白平衡的系统，但程度上 衰老大脑中的哪种蛋白平衡缺失是阿尔茨海默病发病的危险因素 仍然不为人知。我们将专注于伴侣介导的自噬(CMA)，这是一种蛋白质质量控制系统 介导溶酶体中胞浆蛋白的选择性降解。我们之前发现CMA 随着年龄的增长，活性降低，恢复老龄小鼠肝脏的CMA活性可以防止它们的退化和 保护器官功能。 我们认为：1)随着年龄的增长，CMA的生理性衰退增加了衰老的易感性 脑到阿尔茨海默病相关病理以及2)恢复正常CMA活动的干预 大脑老化可防止或延缓阿尔茨海默病的神经退行性变。 为了验证这一假设，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定的“不归路”点； 2)研究神经元CMA阻断是否影响阿尔茨海默病患者的脑表型特征； 3)检测衰老大脑中CMA的遗传或化学增强是否增加其对AD相关的抵抗力 蛋白毒性，改善神经元的动态平衡和功能。 意义：这项研究将阐明CMA功能衰退是如何导致大脑老化的，以及它是否 会增加衰老大脑中患阿尔茨海默氏症的风险。我们的发现可能有助于开发新的方法来 保护旧的大脑动态平衡和功能，降低其对阿尔茨海默氏症神经病理的风险。

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.