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

SNAP 介导的溶酶体调节在阿尔茨海默病发病机制中的作用

• 批准号: 8661657
• 负责人: Qian Cai
• 金额: $ 24.5万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8661657
• 关键词: Aging-Related Process; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Autophagocytosis; Biological; Brain; Cell physiology; Cells; Defect; Deposition; Development; Disease; Dynein ATPase; Functional disorder; Genes; Genetic; Goals; Homeostasis; Instruction; Knowledge; Lead; Life; Link; Lysosomes; Mediating; Membrane Protein Traffic; Mitochondria; Molecular; Motor; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Organelles; Outcome Study; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Play; Prevention; Preventive; Process; Production; Quality Control; Regulation; Research; Role; SNAPIN gene; Synapses; System; Testing; Therapeutic; Transgenic Mice; Translational Research; Up-Regulation; Work; age related; aged; amyloid precursor protein processing; amyloidogenesis; base; endosome membrane; fighting; innovation; insight; late endosome; mitochondrial dysfunction; mouse model; neuropathology; novel; novel therapeutics; protein aggregate; protein metabolism; protein transport; research study; retrograde transport; trafficking

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.

自噬-溶酶体途径对于神经元稳态至关重要。该通路内的缺陷 与越来越多的神经退行性疾病直接相关。溶酶体功能障碍是其中之一 导致阿尔茨海默病 (AD) 发病和进展的主要细胞缺陷。然而，它 目前尚不清楚晚期内吞运输的改变是否会导致淀粉样前体蛋白的异常增加 (APP) 淀粉样蛋白生成过程，从而导致淀粉样蛋白 p-肽 (Ap) 的积累 耐心的大脑。这项工作的目标是确定 APP 中上调的晚期内吞途径的作用 AD 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蛋白生成活性所需的关键步骤 机械，从而控制 AD 大脑中的 Ap 沉积。利用小鼠遗传和细胞生物学 方法结合活神经元的基因拯救实验，我们确定了 Snapin 协调 晚期内体的逆行运输和晚期内吞途径的膜运输，因此 强调了上调神经元自噬溶酶体功能的新机制。的贡献 这项研究预计将增进我们的知识，并提供有关 Snapin 介导的机制的见解 晚期内体-溶酶体运输的上调控制 APP 代谢和 Ap 沉积，以及 消除 AD 模型大脑中受损的线粒体。预计已确定的机制将 提供导致预防和治疗策略的新概念，这将使越来越多的人受益 患有 Ap 沉积或溶酶体病理学以及线粒体功能障碍的 AD 患者 中枢神经系统。预计拟议研究的结果最终将适用 预防和治疗许多与年龄相关的神经退行性疾病 蛋白质聚集体的积累以及功能失调的溶酶体和线粒体。这项工作是一致的 NIA 长期致力于了解衰老过程并对抗与年龄相关的疾病 神经退行性疾病。