Aβ外周清除功能在阿尔茨海默病发生中的作用和机制研究

项目名称： Aβ外周清除功能在阿尔茨海默病发生中的作用和机制研究

项目编号： No.81471296

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王延江

作者单位： 中国人民解放军第三军医大学

项目金额： 70万元

中文摘要： β淀粉样肽(Aβ)在脑内产生过多和/或清除障碍是阿尔茨海默病(AD)发生的主要原因。清除脑内Aβ是AD防治的重要策略。我们把Aβ清除划分为中枢清除和外周清除(Nat Rev Neurol2012),前者指Aβ清除物质进入脑内发挥清除作用,后者指通过清除血液中Aβ而促进脑内Aβ外流和清除。针对Aβ清除的免疫治疗临床试验均失败,其副作用与中枢清除有关,我们提出外周清除是更为安全的防治策略(Nat Rev Neurol2014)。机体具有天然Aβ外周清除能力,但机制及对AD发生的作用不清楚。外周组织产生的Aβ是否进入脑内促进AD发生值得探讨。本项目首先探讨机体外周Aβ清除能力、影响因素及机制;采用APPswe/PS1dE9小鼠和野生型小鼠并联模型,探讨天然Aβ外周清除功能在AD发生中的作用和机制,探讨外周来源Aβ是否促进AD发生。本项目从外周角度探讨AD发生机制,对建立AD防治新策略有重要意义。

中文关键词： 阿尔茨海默病；β淀粉样蛋白；外周清除；发生机制；防治

英文摘要： Overproduction of amyloid-beta(Abeta) and reduced clearance of Abeta deposition in the brain play critical roles in the development of Alzheimer's disease (AD). Removal of brain Abeta deposition is a major therapeutic strategy for AD. Previously we classified the Abeta clearane into central clearance and periperal clearance based on the action site of Abeta-removal agents.Immunotherapy, which targets Abeta clearance, failed in clinical trials, with a series of adverse effects, which were associated with the entry of antibodies into the brain. Thus we proposed that peripheral clearance would be a safer and effective approach to remove Abeta from the brain. The periphal organs and tissues, such as liver, kidney and blood phagocytes, have natural abilities to degrade Abeta from the blood. However, the roles the natural peripheral Abeta clearance in the development of AD, and the underlying mechanisms, remains largely unknown. In addition, Abeta is also produced in peripheral tissues and organs, it is unknown whether this periphery originated Abeta can enter brain and contribute to Abeta deposition in the brain of AD remains unknown. In the present proposal, firstly we will investigate the ability of Abeta clearance in peripheral tissues and organs, and elucidate the relevant mechanisms and impact of aging and gender which are important risk factors for AD. Next,we will study the contribution of peripheal Abeta clearance ability to the accumulation of Abeta deposition in the brain of AD mice by using a parabiosis model which pairs APPswe/PS1dE9 mice and wild type mice. At last we will exam whether Abeta from the paired APPswe/PS1dE9 mouse can enter the brain of paired wild type mice and form Abeta deposition in the brain. The present proposal is important to elucidate the pathogenesis of AD,and to develop novel therapies based on peirpheral Abeta clearance.

英文关键词： Alzheimer's disease;Aβ;peripheral clearance;pathogenesis;therapy