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

摘要 这项建议调查的作用和影响，有缺陷的维持蛋白质稳态 在阿尔茨海默病的发展和进展中，衰老大脑的蛋白质（蛋白质稳态）。扰动 在阿尔茨海默氏病中已经观察到维持神经元蛋白质稳态的系统，但是 衰老大脑中蛋白质稳态的丧失构成了阿尔茨海默病发展的危险因素 仍然未知。我们将集中在分子伴侣介导的自噬（CMA），蛋白质质量控制系统 介导溶酶体中胞质蛋白质的选择性降解。我们之前发现CMA 活性随着年龄的增长而降低，在老年小鼠肝脏中恢复CMA活性可以防止它们的退化， 保持器官功能。 我们认为：（1）CMA随年龄的生理性下降增加了衰老的易感性 脑与阿尔茨海默病相关的病理学和2）干预恢复正常的CMA活动， 老化的大脑将防止或减缓阿尔茨海默病神经变性的进展。 为了验证这一假设，我们打算：1）确定CMA变化的时空序列， 老化大脑，以确定对蛋白质毒性更敏感的区域和蛋白质稳态的“不归路”点; 2)研究阿尔茨海默病大脑的特征是否被神经元CMA阻断所表型模仿; 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相关疾病的抵抗力。 蛋白毒性，并改善神经元的稳态和功能。 意义：本研究将阐明CMA功能下降如何促进脑老化，以及是否 会增加老年痴呆症的风险我们的发现可以帮助开发新的方法， 保持旧的大脑稳态和功能，并降低其患阿尔茨海默病神经病理学的风险。

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.