Cellular function of the amyloid precursor like protein 1 in endocytosis and proteolytic shedding of APP

淀粉样蛋白前体蛋白（APP）胞外区域的蛋白水解裂解是致病性淀粉样蛋白b肽（Ab）生成的关键调控步骤，Ab沉积在阿尔茨海默病患者的大脑中。然而，对于调控APP切割和影响Ab生成的细胞过程，以及它们与疾病发生和进展的联系，我们所知相对较少。为了系统地探索其促进途径，我们进行了表达克隆筛选，并鉴定了几种蛋白质，这些蛋白质刺激所谓的APP的a-裂解，从而可能减少Ab的产生。令人惊讶的是，其中一种蛋白质是淀粉样蛋白前体样蛋白1 (APLP1)，这是APP的同源物。使用分子和细胞生物学技术，本应用程序的目的是详细表征APLP1如何影响APP加工和Ab的产生。此外，我们将分析APLP1刺激APP脱落的细胞机制。我们对控制Ab生成的细胞机制了解得越详细，就越有可能设计出治疗限制Ab生成的策略来治疗阿尔茨海默病。该项目将与优先计划内的其他研究小组合作开展。

Proteolytic cleavage in the extracellular domain of the amyloid precursor protein (APP) is a key regulatory step in the generation of the pathogenic amyloid b peptide (Ab), which is deposited in the brain of Alzheimer's disease patients. However, relatively little is known about the cellular processes that regulate APP cleavage and influence Ab generation, and their connections to disease development and progression. To explore the contributory pathways systematically, we carried out an expression cloning screen and identified several proteins that stimulate the so-called a-cleavage of APP and thus might reduce the generation of Ab. Surprisingly, one of these proteins is the amyloid precursor like protein 1 (APLP1), a homologue of APP. Using molecular and cell biological techniques the aim of this application is to characterize in detail how APLP1 influences APP processing and Ab generation. Moreover, we will analyze the cellular mechanism by which APLP1 stimulates APP shedding. The more detailed we understand the cellular mechanisms controlling Ab generation, the better it will be possible to devise strategies to therapeutically limit Ab generation for treating Alzheimer's disease. The project will be carried out in collaboration with other research groups within the priority program.