PATHOGENESIS OF ALZHEIMERS DISEASE

阿尔茨海默病的发病机制

• 批准号: 2892107
• 负责人: IAN S TROWBRIDGE
• 金额: $ 31.48万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2892107
• 关键词: Alzheimer's disease; amyloid proteins; chimeric proteins; electron microscopy; endocytosis; enzyme inhibitors; fluorescence microscopy; guanosinetriphosphatases; immunoprecipitation; intracellular transport; laboratory rat; membrane proteins; mutant; phosphatidylinositol 3 kinase; protein sequence; protein transport; tissue /cell culture; transferrin receptor; western blottings

The long term goal of the proposed research is to understand the role of the B- amyloid precursor protein (APP) trafficking in the pathogenesis of Alzheimer's disease. Recent studies have established that APP is an itinerant membrane protein which displays multiple cytoplasmic sorting signals. The cytoplasm tail of APP contains a sequence GYENPTY related to the 6-residue LDLR internalization signal FDNPVY as well as the segment YTSI which conforms the 4-residue tyrosine-based internalization consensus sequence. These signals are recognized by molecular sorting machinery located at different sites within the cell and determine the intracellular trafficking pathways along which APP is routed. Although there is evidence that AB can be generated from APP expressed on the cell surface and that internalization is required, it is unclear whether this is the exclusive or even the major trafficking pathway leading to the production of AB. The primary objectives of the present application are to determine how trafficking of APP influences AB production and whether APP trafficking is regulated by other gene products implicated in the pathogenesis of AD. To accomplish these goals, the PI will take advantage of emerging conceptual and methodological advances in the field of membrane protein sorting and apply them to APP trafficking. The major experimental approach will be to exploit transferrin receptor (TR) chimers including APP-TR chimera that all quantitative biochemical and morphological studies of membrane proteins to performed. The use of the TR chimeras allows unique properties of this receptor-ligand system to be used to define membrane protein trafficking under a variety of experimental conditions. The methods developed to modify protein trafficking through the study of TR chimeras will be used to determine how altered APP trafficking affects AB production.

拟议研究的长期目标是了解其作用 B-淀粉样前体蛋白（APP）在 阿尔茨海默病的发病机制。 最近的研究已经确定 APP 是一种巡回膜蛋白，可显示多种 细胞质分选信号。 APP 的细胞质尾部含有 与 6 残基 LDLR 内化信号相关的序列 GYENPTY FDNPVY 以及符合 4 残基的 YTSI 片段 基于酪氨酸的内化共有序列。 这些信号是 被位于不同地点的分子分选机器识别 细胞内并确定细胞内运输途径 APP 沿其路由。 尽管有证据表明AB可以 由细胞表面表达的 APP 生成，并且 需要内部化，目前还不清楚这是否是排他性的 甚至是导致 AB 生产的主要贩运途径。 本申请的主要目的是确定如何 APP 的贩运影响 AB 生产以及 APP 是否 贩运受到与该基因相关的其他基因产品的调节 AD的发病机制。 为了实现这些目标，PI 将采取 新兴概念和方法论进步的优势 膜蛋白分选领域并将其应用于APP贩运。 主要的实验方法是利用转铁蛋白受体 (TR)嵌合体包括APP-TR嵌合体，所有定量生化 以及膜蛋白的形态学研究。 用途 TR 嵌合体的独特特性使得该受体-配体具有独特的特性 系统用于定义各种膜蛋白运输 的实验条件。 开发的修饰蛋白质的方法 通过 TR 嵌合体研究进行的贩运将用于确定 APP 贩运的改变如何影响 AB 生产。