CHOLESTEROL EFFECTS ON HUMAN ApoE AND APP INTERACTIONS

胆固醇对人类 ApoE 和应用程序相互作用的影响

• 批准号: 6479982
• 负责人: PATRICK M SULLIVAN
• 金额: $ 31.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479982
• 关键词: Alzheimer's disease; amyloid proteins; apolipoprotein E; brain metabolism; cholesterol; dietary lipid; disease /disorder model; disease /disorder onset; disease /disorder proneness /risk; gene environment interaction; gene interaction; genetic models; genetic strain; genetic susceptibility; genetic transcription; genetically modified animals; human tissue; laboratory mouse; model design /development; northern blottings; nutrition related tag; protein isoforms; protein metabolism; protein protein interaction

This project proposes to test the hypothesis that apoE and cholesterol modify Abeta deposition in an isoform-dependent fashion with the apoE4 allele acting in a dominant mode. Rare mutations in amyloid precursor protein (APP) are responsible for some cases of early onset autosomal dominant Alzheimer's disease (AD). Isoform differences at the AD susceptibility gene apolipoprotein (apo) E locus affect age of onset for late on-set AD, and may influence from 15-50% of all cases. In humans, there are three major apoE isoforms designated apoE2, E3, and E4 that differ by a single amino acid. ApoE functions to maintain cholesterol and fat homeostasis. ApoE isoforms also interact either directly or indirectly with APP to modulate the extent of Abeta deposition associated with one dimension of AD pathology. Current human studies suggest that high cholesterol increases the risk of AD. Animal studies reveal significant effects of cholesterol on APP and apoE metabolism in the brain, and on Abeta deposition, and suggest a major environmental (i.e. dietary fat and cholesterol) may modify AD pathology. We have transgenic animal models to test this hypothesis, human apoE targeted replacement mice, human apoE transgenic mice and the human APPV717F transgenic mouse. ApoE isoform-specific promoter effects on brain apoE levels will be measured under basal and high cholesterol conditions. AD-related pathology will be examined by crossing the apoE targeted replacement animals to mice bearing a human APP mutation using Abeta deposition and APP metabolism as endpoints. Finally, the ability to create animal models of the common human heterozygote, APOE3/4, will allow testing for dominant-positive or dominant-negative effects of human apoE isoforms. Modeling dietary factors that may modulate APP and apoE will advance the understanding of environmental and genetic interactions that influence the onset and progression of AD.

该项目提议测试以下假设：ApoE和胆固醇以同工型依赖性的方式修饰Abeta沉积，其APOE4等位基因作用于显性模式。淀粉样蛋白前体蛋白（APP）中的罕见突变导致某些早期发作常染色体显性阿尔茨海默氏病（AD）的原因。 AD易感性基因载脂蛋白（APO）E基因座的同工型差异会影响晚期AD的发作年龄，并且可能影响所有病例的15-50％。在人类中，指定APOE2，E3和E4的三种主要APOE同工型与单个氨基酸不同。 APOE功能可维持胆固醇和脂肪稳态。 APOE同工型还与APP直接或间接相互作用，以调节与AD病理一维相关的ABETA沉积程度。当前的人类研究表明，高胆固醇会增加AD的风险。动物研究揭示了胆固醇对大脑中APP和APOE代谢以及ABETA沉积的显着影响，并提示主要的环境（即饮食中的脂肪和胆固醇）可能会改变AD病理。我们有转基因动物模型来检验该假设，人APOE靶向替代小鼠，人ApoE转基因小鼠和人类Appv717F转基因小鼠。 APOE同工型特异性启动子对脑APOE水平的影响将在基础和高胆固醇条件下测量。通过将APOE靶向替代动物跨到具有ABETA沉积和APP代谢作为终点的小鼠的小鼠，将检查与广告相关的病理。最后，创建共同人类杂合子APOE3/4动物模型的能力将允许测试人类APOE同工型的显性阳性或显性阴性作用。建模可能调节APP和APOE的饮食因素将提高对影响AD发作和进展的环境和遗传相互作用的理解。