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

淀粉样前体蛋白(APP)胞外区域的蛋白水解性切割是产生致病淀粉样蛋白b(Ab)的关键调控步骤，该蛋白沉积在阿尔茨海默病患者的大脑中。然而，对调节APP切割并影响抗体生成的细胞过程以及它们与疾病发展和进展的关系知之甚少。为了系统地探索APP的作用途径，我们进行了表达克隆筛选，并鉴定了几种刺激APP的a-裂解从而可能减少抗体的产生的蛋白质。令人惊讶的是，其中一种蛋白质是淀粉样前体蛋白1(APLP1)，它是APP的同源物。利用分子和细胞生物学技术，这项应用的目的是详细描述APLP1如何影响APP的处理和抗体的产生。此外，我们还将分析APLP1刺激APP脱落的细胞机制。我们对控制抗体生成的细胞机制了解得越详细，就越有可能设计出治疗阿尔茨海默病的方法来限制抗体的生成。该项目将与优先方案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.