PATHOGENESIS OF ALZHEIMERS DISEASE

拟议研究的长期目标是了解 B- 淀粉样前体蛋白（APP）运输在阿尔茨海默病发病机制中的作用 S 疾病 最近的研究表明APP是一种流动膜 显示多个细胞质分选信号的蛋白质。 细胞质 APP的尾部含有与6个残基LDLR相关的序列GYENPTY 内化信号FDNPVY以及符合上述信号的片段YTSI， 4- 基于残基酪氨酸的内化共有序列。 这些信号A 由位于不同位点的分子分选机器识别， 他 细胞，并确定细胞内运输途径，其中APP是沿着 路由。 虽然有证据表明AB可以从APP表达中产生，但它可能是一种免疫抑制剂。 艾德 在细胞表面，需要内化，目前还不清楚， 儿 这是唯一的甚至是主要的贩运途径， 生产AB。 本申请的主要目的是 确定APP的贩运如何影响AB生产，以及APP是否 运输受致病基因中涉及的其他基因产物的调节 S 的AD。 为了实现这些目标，PI将利用新兴的 膜蛋白分选领域的概念和方法学进展 ng 并将其应用于APP贩运。 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学研究， 执行。 TR嵌合体的使用使得这种重组蛋白具有独特的性质， 或， 配体系统用于定义在不同的 Ty 的实验条件。 改变蛋白质运输的方法 ing 通过对TR嵌合体的研究， 贩运影响AB生产。

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.