膳食胆固醇及其氧化代谢产物在阿尔茨海默病发病过程中的作用及其相关机制研究

项目名称： 膳食胆固醇及其氧化代谢产物在阿尔茨海默病发病过程中的作用及其相关机制研究

项目编号： No.81330065

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 肖荣

作者单位： 首都医科大学

项目金额： 290万元

中文摘要： 膳食胆固醇与以认知障碍为特征的阿尔茨海默病有关，但作用机制不清。课题组前期研究表明β-淀粉样肽（Aβ）可引起脑内胆固醇清除增强和转运障碍，过量摄入膳食胆固醇可引起学习记忆能力下降，提示膳食胆固醇、Aβ和脑内胆固醇与学习记忆障碍有关。本项目拟用Aβ代谢障碍和胆固醇代谢紊乱转基因鼠、长期高胆固醇喂饲老年鼠以及神经细胞和星形胶质细胞单独或共培养体系，分别检测神经行为、胆固醇合成和转运、Aβ生成与内吞、脂质筏结构与功能、突触可塑性、氧化应激和炎症反应相关指标，探讨过量膳食胆固醇通过其氧化代谢产物损伤学习记忆能力的机制；通过前瞻性和双向队列研究，检测并分析膳食胆固醇摄入量、血氧化固醇水平及关键酶的基因型和氧化固醇谱的变化与认知障碍的关系；通过实验室及人群研究验证膳食胆固醇摄入过量，引起血清和脑组织氧化固醇堆积，干扰了Aβ代谢，促进AD发病的假说，为研究膳食胆固醇需求与健康和AD预防提供科学数据。

中文关键词： 膳食胆固醇;阿尔茨海默病;脑内胆固醇转运;氧化固醇;营养素需求

英文摘要： High cholesterol may increase the risk of developing Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive disorder. Mechanisms underlying are unclear. The previous studies indicated that there might be a link between dietary cholesterol, β amyloid peptide (Aβ), and disorder of the brain cholesterol metabolism. In this project, to explore the underlying mechanism of dietary cholesterol to promote AD, transgenic mice with Amyloid Precursor Protein (APP), ApoE deficient mice, and double transgenic mice will be used to investigate (1) the effects of dietary cholesterol and oxysterol on β-amyloid metabolism, oxidative stress and inflammation, and AD progression; (2) the effects of β-amyloid peptides on the cholesterol transportation and metabolism between neuron and astrocyte; (3) the impact on memory and learning ability. Neuronal cells and astrocytes were cultured or co-cultured to determine the effects of oxysterol on cholesterol synthesis and transportation, neuron structure and function, and synapse plastisity. We will investigate the relationship of serum cholesterol and oxysterol level, dietary cholesterol intake with the recognition decline in healthy middle life volunteers and in community-dwelling older people. The oxysterolomics character of healthy people and AD patients will be analyzed using GC-MS. Based on these expected results, we will understand the relationship and mechanism of dietary cholesterol intake and incidence of AD to provide scientific evidence for prophylaxis treatment of AD.

英文关键词： dietary Cholesterol ;Alzheimer's disease;brain cholesterol transport;oxysterol;nutrients requirment