阿尔茨海默病中APP蛋白的转运调控研究

项目名称： 阿尔茨海默病中APP蛋白的转运调控研究

项目编号： No.U1405222

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 许华曦

作者单位： 厦门大学

项目金额： 256万元

中文摘要： Abeta过量产生是导致阿尔茨海默病AD的关键。Abeta是由其前体蛋白APP在细胞内转运的过程中被beta-和gamma-分泌酶依次剪切后产生。APP的转运发生异常以及APP突变会影响Abeta产生，导致AD。我们及他人发现SNX27、SorL1和Retromer复合体均可以调控APP的转运。前期结果显示这三者之间能够相互结合。我们提出假说认为SNX27、SorL1、Retromer三者之间通过相互作用，协调一致地调控APP的转运和剪切；其中任意一个发生异常，都会影响其它二者的正常功能，进而干扰APP的转运/剪切和Abeta产生，引发疾病。我们与台湾合作者将验证这一假说，并探讨APP突变是否会通过SNX27、SorL1和Retromer的介导，影响APP自身的细胞内定位。我们还将研究过表达SNX27是否可以改善AD疾病症状和抑制因SorL1或Retromer缺失所导致的AD疾病进程加速。

中文关键词： 阿尔茨海默病；APP蛋白；蛋白转运；SNX27蛋白；SorL1蛋白

英文摘要： Overproduction and aggregation of Abeta in vulnerable brain regions is crucial for the pathogenesis of Alzheimer’s disease (AD). Abeta is derived from its precursor protein APP through sequential cleavages by beta- and gamma-secretases during APP trafficking within the cell. Dysregulation of APP intracellular trafficking, as well as APP mutations may affect Abeta generation and lead to disease pathogenesis. We and others have found that intracellular trafficking of APP can be regulated by SNX27, SorL1 and the VPS35 retromer. In our preliminary study, we also found that SNX27, SorL1 and the VPS35 retromer can interact with each other. Herein, we hypothesize that SNX27, SorL1 and the VPS35 retromer coordinately regulate APP trafficking through their interaction and that deficiency in any of them may affect the other two and hence alter APP trafficking/processing and Abeta production. In this study, we and our collaborator from Taiwan will validate this hypothesis and determine whether certain mutations in APP affect its own subcellular localization through mediation by SNX27, SorL1 and the VPS35 retromer. Moreover, we will investigate whether overexpression of SNX27 can ameliorate disease-like phenotypes in AD mice and delay early-onset disease phenotypes caused by SorL1- and VPS35-deficiency. Such study will provide valuable insights into the mechanisms underlying AD pathogenesis and provide new potential targets for treatment strategies.

英文关键词： NULL