REGULATION OF AMYLOID BETA PROTEIN BY APOE & CHOLESTEROL

APOE 对淀粉样β蛋白的调节

• 批准号: 6629866
• 负责人: Bruce A YANKNER
• 金额: $ 33.5万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629866
• 关键词: Alzheimer's disease; aging; amyloid proteins; antihypercholesterolemic agent; apolipoprotein E; brain metabolism; cholesterol; dietary lipid; gene mutation; genetically modified animals; human tissue; laboratory mouse; low density lipoprotein receptor; mental disorder chemotherapy; nutrition related tag; presenilin; protein metabolism; stem cells; tissue /cell culture

DESCRIPTION: (Verbatim from the Applicant's Abstract) Inheritance of the E4 allele of apolipoprotein E (apoE) is the most prevalent genetic risk factor for Alzheimer's disease (AD) and is associated with increased deposition of amyloid B protein (AB). The goal of this proposal is to elucidate the role of apoE in the metabolism of AB and amyloid precursor protein (APP) and its control by dietary cholesterol. The studies in this proposal are based on the working hypothesis that the absolute level of apoE is a major determinant of AB levels in the brain and can be regulated by dietary cholesterol. Our preliminary studies show that physiological concentrations of apoE significantly elevate the levels of the 40 and 42 amino acid forms of AB in human cortical cultures due to inhibition of AB degradation. Moreover, rats fed a high cholesterol diet show significantly elevated apoE levels in the cerebral cortex and altered processing of APP. These findings suggest that increased cortical apoE, which can be induced by a high cholesterol diet, may predispose to AB deposition and the onset of AD. The effect of apoE on the cortical metabolism of AB and APP will be investigated in apoE-knockout and apoE3 and apoE4-transgenic mice. We will determine whether apoE has the greatest effect on AB metabolism in the aging brain, and whether this effect can be modulated by dietary cholesterol. These studies will be complemented by an investigation of the effects of apoE and dietary cholesterol on plaque formation in APP-transgenic mice, and the examination of potential therapeutic approaches utilizing cholesterol-lowering drugs and neural stem cells that can scavenge apoE. The effect of a high cholesterol diet on AB production in transgenic mice that express disease-causing presenilin-1 mutations will also be examined. To elucidate the mechanism by which apoE inhibits AB degradation; the receptors and soluble factors that mediate AB clearance will be identified in primary human cortical cultures. Known candidate receptors that could mediate AB uptake, including the LDL receptor-related protein, the microglial scavenger receptor and the serpin-enzyme complex receptor, will be examined, as well as novel AB uptake receptors. These studies may help to elucidate the roles of apoE and dietary cholesterol in the pathogenesis of AD, with potentially important implications for early genotyping and therapeutic intervention.

描述：（逐字摘自申请人摘要）E4 的继承 载脂蛋白 E (apoE) 等位基因是最常见的遗传风险因素 阿尔茨海默病 (AD) 与淀粉样蛋白沉积增加有关 B蛋白（AB）。该提案的目标是阐明 apoE 在 AB 和淀粉样前体蛋白 (APP) 的代谢及其控制 膳食胆固醇。本提案中的研究基于工作 假设 apoE 的绝对水平是 AB 水平的主要决定因素 在大脑中，可以通过饮食胆固醇进行调节。我们的初步 研究表明，apoE 的生理浓度显着升高 人类皮质培养物中 40 和 42 氨基酸形式的 AB 水平 由于抑制 AB 降解。此外，老鼠喂食高胆固醇饮食 大脑皮层中的 apoE 水平显着升高并发生改变 APP处理。这些发现表明皮质 apoE 增加， 可由高胆固醇饮食诱发，可能导致 AB 沉积， AD 的发作。 apoE对AB和APP皮质代谢的影响 将在 apoE 敲除小鼠以及 apoE3 和 apoE4 转基因小鼠中进行研究。我们 将确定 apoE 是否对 AB 代谢具有最大影响 大脑老化，以及这种效应是否可以通过饮食胆固醇调节。 这些研究将通过对 apoE 影响的调查得到补充 和膳食胆固醇对 APP 转基因小鼠斑块形成的影响，以及 检查利用降低胆固醇的潜在治疗方法 可以清除apoE的药物和神经干细胞。高的效果 胆固醇饮食对转基因小鼠AB产生的影响 还将检查引起疾病的 presenilin-1 突变。为了阐明 apoE 抑制 AB 降解的机制；受体和可溶性 介导 AB 清除的因素将在初级人类皮质中被确定 文化。已知的候选受体可以介导 AB 摄取，包括 LDL受体相关蛋白、小胶质细胞清道夫受体和 丝氨酸蛋白酶抑制剂-酶复合物受体，以及新的 AB 摄取将被检查 受体。这些研究可能有助于阐明 apoE 和饮食的作用 胆固醇在 AD 发病机制中的作用，具有潜在的重要意义 用于早期基因分型和治疗干预。