Vesicular transport of the amyloid precursor protein

描述(申请人提供)：阿尔茨海默病(AD)的一个主要特征是含有抗体的老年斑，它是由淀粉样前体蛋白(APP)加工形成的。细胞内运输在APP的处理中起着至关重要的作用，但控制APP细胞内交通的机制仍然不够清楚。两种蛋白质，薄荷和FE65在APP的加工过程中扮演着相反的角色：薄荷抑制和FE65增加抗体的产生。最近的数据表明，薄荷糖可能作为一种囊泡外壳蛋白发挥作用，因此薄荷糖可能通过控制应用程序流量来调节应用程序的处理。这项提案将建立生化分析，以确定涉及囊泡运输的分子成分。膜募集试验将被用来检验APP作为一种货物受体，以一种ARF依赖的方式将薄荷糖募集到膜上的假设，而FE65可以阻止这种方式。将进行体外发芽试验，以确定含APP的囊泡的发芽是否需要ARF和薄荷糖。由于APP的处理依赖于APP的贩运，这些数据将阐明APP被靶向非致病途径的机制，从而确定AD的新治疗靶点。

DESCRIPTION (provided by applicant): One of the primary characteristics of Alzheimer's disease (AD) is senile plaques containing Ab which is formed by the processing of amyloid precursor protein (APP). Intracellular transport plays a crucial role in APP processing, but the mechanisms involved in controlling APP intracellular traffic remain insufficiently characterized. Two proteins, Mints and FE65 play opposite roles in APP processing: Mints inhibit and FE65 increases the production of Ab. Recent data suggest that Mints may function as a vesicular coat protein and thus Mints may regulate APP processing by controlling APP traffic. This proposal will establish biochemical assays that will define the molecular components involved APP vesicular trafficking. Membrane recruitment assays will be used to test the hypothesis that APP acts as a cargo receptor that recruits Mints to the membrane in an ARF-dependent manner that is prevented by FE65. In vitro budding assays will be performed to determine if the budding of APP-containing vesicles requires ARF and Mints. Because APP processing depends on APP trafficking, these data will elucidate the mechanisms by which APP is targeted to a nonpathogenic pathway and consequently identify novel therapeutic targets for AD.