HSPG受体途径影响脂质化载脂蛋白E亚型调控β-淀粉样蛋白代谢作用的相关机制研究

项目名称： HSPG受体途径影响脂质化载脂蛋白E亚型调控β-淀粉样蛋白代谢作用的相关机制研究

项目编号： No.81500917

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： 付源

作者单位： 哈尔滨医科大学

项目金额： 21万元

中文摘要： β-淀粉样蛋白（Aβ）是阿尔茨海默病（AD）最为重要的致病物质，载脂蛋白E（ApoE）通过调节Aβ代谢参与AD的发病机制，其中脂质化、亚型依赖性，和受体途径是其发挥调节功能的重要因素，原因不明。最新研究和我们前期工作表明：①在生理条件下只有极少量的脂质化ApoE与Aβ结合；②脂质化ApoE与肝素具有高亲和力；③脂质化ApoE可降低小鼠神经元摄取Aβ，并拮抗Aβ多聚物的毒性。结合前期工作和现有对AD发病机制的认识，本项目以纯化的脂质化ApoE为研究对象，从全新的角度探讨其在硫酸乙酰肝素蛋白聚糖（HSPG）受体途径上如何调控Aβ代谢及相关机制。通过本项目，我们将解决：①脂质化ApoE的细胞摄取和其调节Aβ代谢及毒性的亚型依赖性；②HSPG受体途径对细胞摄取脂质化ApoE和Aβ的影响；③HSPG受体途径对脂质化ApoE调节Aβ代谢的影响。这些问题的解决将为AD临床治疗提供重要的理论基础和新策略。

中文关键词： β-淀粉样蛋白；载脂蛋白E；阿尔茨海默病；硫酸乙酰肝素蛋白聚糖；细胞摄取

英文摘要： Amyloid-β deposition is the most significant pathological factor of Alzheimer’s disease(AD), regulated by apolipoprotein E (ApoE) which is involved in the pathogenesis of AD through modulating the production and clearance of Aβ. Lipidation, isoform-dependence and receptor pathways are important factors that influence the effect of ApoE, however the detailed mechanisms remain elusive. Recent studies and our previous work indicate that: ① Aβ is an extremely poor binding partner of lipidated ApoE isoforms in physiological conditions; ② lipidated ApoE binds to heparin with high affinity; ③ lipidated ApoE decreases the uptake of Aβ in mouse neurons. In this proposal, regarding to our previous studies and current understanding to the pathogenesis of AD, we innovatively use purified lipidated ApoE as the target to study how the HSPG receptor pathway influences the effect of ApoE on the metabolism of Aβ. We aim to comprehensively address these vital questions: ① whether the cellular uptake of lipidated ApoE and its ability to modulate the metabolism and toxicity of Aβ are isoform-dependent; ② how the HSPG pathway influences the cellular uptake of lipidated ApoE and Aβ; ③ whether the HSPG receptor pathway influences the effect of ApoE to the metabolism of Aβ and the possible mechanisms. Thereby solving these problems, our study will provide important theoretical foundations and new strategies to AD therapy.

英文关键词： Amyloid-β;Apolipoprotein E ;Alzheimer's disease;Heparan Sulfate Proteoglycan(HSPG);Cellular uptake