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体内平衡至关重要。该路径内的缺陷 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 主要的细胞缺陷导致阿尔茨海默氏病（AD）的发作和进展。但是，它 目前尚不清楚晚期内吞运输是否会导致淀粉样前体蛋白异常增加 （APP）淀粉样蛋白生成加工，从而导致淀粉样蛋白P肽（AP）在 病人的大脑。这项工作的目的是定义应用中上调的晚期内吞途径的作用 AD发作和进展过程中的处理和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酶活性所需的关键步骤 机械，从而控制AD大脑中的AP沉积。使用小鼠遗传和细胞生物学 方法与活神经元中的基因救援实验结合在一起，我们确定了Snapin坐标 后期内体的逆行运输和晚期内吞途径的膜运输，因此 突出了一种新的机制，用于上调神经元自噬溶质体功能。的贡献 预计这项研究将提高我们的知识，并提供有关Snapin介导的方式的机械见解 晚期内体 - 赖斯体贩运控制的上调APP代谢和AP沉积，以及 消除了AD模型大脑中的线粒体受损。预计确定的机制将 提供新的概念，导致预防和治疗策略，将有益于日益增长的数量 患有AP沉积或溶酶体病理学和线粒体功能障碍的AD患者 中枢神经系统。预计拟议研究的发现最终将适用 预防和治疗许多与年龄有关的神经退行性疾病 蛋白质聚集体和功能障碍溶酶体和线粒体的积累。这项工作是一致的 NIA长期承诺了解衰老过程并与年龄有关 神经退行性疾病。