PATHOGENESIS OF ALZHEIMERS DISEASE

阿尔茨海默病的发病机制

• 批准号: 2445863
• 负责人: IAN S TROWBRIDGE
• 金额: $ 25.88万
• 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 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445863
• 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 th B- amyloid precursor protein (APP) trafficking in the pathogenesis of Alzheime 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 th 4- residue tyrosine-based internalization consensus sequence. These signals a recognized by molecular sorting machinery located at different sites within he cell and determine the intracellular trafficking pathways along which APP i routed. Although there is evidence that AB can be generated from APP expre ed on the cell surface and that internalization is required, it is unclear whe er 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 pathogene s of AD. To accomplish these goals, the PI will take advantage of emerging conceptual and methodological advances in the field of membrane protein sor ng and apply them to APP trafficking. The major experimental approach will be o 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 rec tor- ligand system to be used to define membrane protein trafficking under a var ty of experimental conditions. The methods developed to modify protein traffi ing 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 B- 淀粉样前体蛋白(APP)转运在阿尔茨海默病发病中的作用 S 疾病。最近的研究证实，APP是一种巡回膜 显示多种细胞质分选信号的蛋白质。细胞质 APP的尾部包含与6-残基LDLR相关的序列GYENPTY 内化信号FDNPVY以及符合 4- 基于残基酪氨酸的内化共识序列。这些信号是 由位于不同地点的分子分选机器识别 他 并确定APP I在细胞内的运输路径 被击溃了。尽管有证据表明AB可以通过APP Express生成 边缘 以及是否需要内化，目前还不清楚什么时候 急诊室 这是唯一的，甚至是主要的人口贩运途径 AB的生产。本申请的主要目标是 确定APP的贩运如何影响AB生产，以及APP是否 走私受到与病原体有关的其他基因产物的调控。 S 公元一代的。为了实现这些目标，PI将利用新兴的 膜蛋白SOR研究的概念和方法进展 Ng 并将其应用于应用程序交易。主要的实验方法将是 O 利用转铁蛋白受体(Tr)嵌合体，包括APP-tr嵌合体 膜蛋白的定量生化和形态研究 已执行。Tr嵌合体的使用允许该rec的独特属性 托尔- 用于确定变异性下膜蛋白转运的配基系统 泰伊 实验条件。为修改蛋白质流量而开发的方法 英 通过对TR嵌合体的研究，将用来确定APP如何改变 人口贩运会影响AB的生产。