ROLE OF SNAPIN-MEDIATED LYSOSOMAL REGULATION IN ALZHEIMER'S DISEASE PATHOGENESIS

自噬-溶酶体途径是神经元内稳态所必需的。这条通路中的缺陷已经 与越来越多的神经退行性疾病有直接联系。溶酶体功能障碍是 导致阿尔茨海默病(AD)发生和发展的主要细胞缺陷。然而，它 目前尚不清楚晚期内吞转运改变是否导致淀粉样前体蛋白异常增加 (APP)产生淀粉样蛋白，从而导致淀粉样蛋白P-肽(AP)在 耐心的大脑。这项工作的目标是确定上调的晚期内吞途径在APP中的作用 阿尔茨海默病发病和进展过程中的加工和AP积累。我的中心假设是 自噬-溶酶体功能是调节淀粉样变活性所需的关键步骤 从而控制阿尔茨海默病大脑中AP的沉积。利用小鼠的遗传和细胞生物学 结合活体神经元的基因拯救实验，我们建立了Snapin坐标 晚期内小体的逆行运输和晚期内吞途径的膜运输，因此 强调一种上调神经元自噬的新机制--溶酶体功能。的贡献 这项研究有望推进我们的知识，并提供关于管理单元如何介导的机械性见解 晚期内酶体-溶酶体转运的上调控制APP代谢和AP沉积，以及 消除阿尔茨海默病模型脑内受损的线粒体。已确定的机制预计将 提供导致预防和治疗战略的新概念，使越来越多的 有AP沉积或溶酶体病理和线粒体功能障碍的AD患者 中枢神经系统。预计拟议研究的结果最终将适用于 预防和治疗许多与年龄相关的神经退行性疾病 蛋白质聚集体和功能失调的溶酶体和线粒体的积累。这项工作是一贯的 NIA长期致力于了解衰老过程并与年龄相关的疾病作斗争 神经退行性疾病。

The autophagy-lysosomal pathway is essential for neuronal homeostasis. Defects within this pathway have been directly linked to a growing number of neurodegenerative diseases. Lysosomal dysfunction is one of the main cellular defects contributing to the onset and progression of Alzheimer's Disease (AD). However, it is unclear if altered late endocytic trafficking leads to the aberrant increase of Amyloid Precursor Protein (APP) amyloidogenic processing, and thereby results in the accumulation of Amyloid p-peptide (Ap) in patient brains. The goal of this work is to define the role of an up-regulated late endocytic pathway in APP processing and Ap accumulation during the onset and progression of AD. My central hypothesis is that autophagy-lysosomal function is a critical step required to regulate the activity of the amyloidogenic machinery and, thus, control Ap deposition in AD brains. Using mouse genetic and cell biological approaches combined with gene rescue experiments in live neurons, we established that Snapin coordinates retrograde transport of late endosomes and membrane trafficking ofthe late endocytic pathway, thus highlighting a novel mechanism for up-regulating neuronal autophagy-lysosomal function. The contribution of this study is expected to advance our knowledge and provide mechanistic insights into how Snapin-mediated up-regulation of late endosome-lysosomal trafficking controls APP metabolism and Ap deposition, and eliminates damaged mitochondria in the brain of AD models. The identified mechanisms are expected to provide new concepts leading to preventive and therapeutic strategies that will benefit the growing number of AD patients who have either Ap deposition or lysosomal pathology and mitochondrial dysfunction in the central nervous system. It is expected that the findings from the proposed study will ultimately be applicable to the prevention and treatment of many age-related neurodegenerative diseases associated with the accumulation of protein aggregates and dysfunctional lysosomes and mitochondria. This work is consistent with the longstanding commitment ofthe NIA to understand the aging process and fight age-related neurodegenerative diseases.