APOE基因多态性对阿尔茨海默病中特化促消退介质的影响

项目名称： APOE基因多态性对阿尔茨海默病中特化促消退介质的影响

项目编号： No.81501089

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 王修哲

作者单位： 上海交通大学

项目金额： 17.5万元

中文摘要： 阿尔茨海默病 (AD) 是一种累及中枢神经系统的神经退行性变性疾病，也是最常见的痴呆致病原因。 载脂蛋白E (APOE) 基因多态性与AD的发病密切相关。APOE4基因型可以将AD的发病风险增多到12倍。APOE4基因影响AD的作用机制尚不明确，但可能与脂类代谢及炎症有关。研究发现，AD病人的脑及脑脊液中的一类称作特化促消退介质 (specialized pro-resolving mediators, SPMs) 的多不饱和脂肪酸衍生物水平减低，并且脑脊液中的SPMs水平与认知水平呈正相关。前期预实验发现，APOE4基因型可以减低AD病人的SPMs合成及其受体表达水平，而SPMs对神经元有保护作用。本课题拟研究APOE基因多态性对中枢神经系统中SPMs的代谢和受体表达的影响，以及这种影响可能造成的AD相关作用，为探究AD的病因学机制及开发以SPMs治疗AD的新思路提供支持。

中文关键词： 阿尔茨海默病；载脂蛋白E；神经元；星形胶质细胞；特化促消退介质

英文摘要： Alzheimer’s disease (AD) is a neurodegenerative disorder that affects the central nervous system, and is the most common cause of dementia. The gene polymorphism of Apolipoprotein E (ApoE) is related to AD. Genotype of APOE4 increases the risk of AD by about 12 times, and makes the development of AD in a younger age. The mechanism of how APOE polymorphism influeces AD is still elusive, but may be related to its effects on lipids and inflammation. Recently, it was found that the levels of specialized pro-resolving mediators (SPMs), a type of metabolites from polyunsaturated fatty acids, are reduced in the brain and cerebral-spinal fluid (CSF) of AD patients, and the levels of SPMs in the CSF are correlated to cognitive scores in a positive manner. In our pilot study, we found APOE4 genotype reduced SPM release and altered SPM receptor expression. On the other hand, SPMs could protect neurons from basal and stimulated conditions. The present project aims to study the effects of APOE polymorphism on metabolisms and signaling of SPMs, as well as the consequential results of such effects on AD, and thus, provides new evidence to AD etiology and novel therapeutic methods for AD based on SPMs.

英文关键词： Alzheimer's disease;ApoE;neuron;astrocyte;specialized pro-resolving mediators