CHOLESTEROL, CAFFEINE AND ALZHEIMER DISEASE-LIKE PATHOLOGY IN RABBIT BRAIN

兔脑中的胆固醇、咖啡因和阿尔茨海默病样病理学

• 批准号: 8360140
• 负责人: OTHMAN GHRIBI
• 金额: $ 24.87万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360140
• 关键词: Adenosine A2A Receptor; Affect; Alzheimer' s Disease; Amyloid; Attenuated; Brain; Caffeine; Calcium; Calcium Channel; Cholesterol; Complex; Diet; Dose; Funding; Gene Mutation; Genes; Grant; ITPR1 gene; Inositol; Lead; Mutation; National Center for Research Resources; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oryctolagus cuniculus; Pathogenesis; Pathology; Prevention; Principal Investigator; Research; Research Infrastructure; Resources; Risk; Ryanodine Receptors; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Work; amyloid peptide; cost; familial Alzheimer disease; feeding; hypercholesterolemia; oxidative damage; receptor; tau Proteins; tau aggregation; tau phosphorylation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis and for which there is limited therapeutic intervention. The major pathological hallmarks of AD are the accumulations of B-amyloid (AB) peptide, the hyperphosphorylation of tau, and neuronal damage. Accumulation of AB may be particularly important because mutations in specific genes, as occur in familial AD, are associated with increased AB levels. While these genetic mutations are responsible for the accumulation of AB in familial AD, the causative factors for increased levels of AB in most cases of AD are not known. Hypercholesterolemia and caffeine are two factors that are capable of modulating AB levels and may affect the pathogenesis of AD. Our longterm objectives are to identify risks and mechanisms by which these factors contribute to the pathology of AD. The objective of this proposal is to determine the extent to which and the mechanisms by which cholesterol-enriched diet triggers and caffeine attenuates or exacerbates AD-like pathology in rabbit brain. The hypotheses to be tested in this proposal are (1) that cholesterol-enriched diets cause B-amyloid (AB) accumulation, tau hyperphosphorylation and neurodegeneration involving modulation of adenosine A2A receptors (A2AR), inositol-1,4,5-trisphosphate receptors (IP3R), and ryanodine receptors (RyR), and (2) that caffeine-induced blockage of A2AR or blockade of calcium release through IP3R will attenuate and caffeine-induced release of calcium from RyR-regulated calcium channels will exacerbate AB accumulation, tau hyperphosphorylation and neurodegeneration. Our specific aims are as follows: Aim 1: Determine the extent to which the expression of A2AR, RyR and IP3R is altered in brain of rabbits fed a diet enriched in cholesterol; Aim 2: Determine the extent to which caffeine dose-dependently regulates cholesterol-induced AD-like pathology and modulates A2AR, RyR and IP3R in rabbit brain; and Aim 3: Determine the extent to which A2AR, RyR and IP3R are involved in cholesterol-induced AB accumulation, tau phosphorylation and oxidative damage. Successful completion of the work proposed here will increase our understanding of the cellular mechanisms by which two factors, cholesterol and caffeine, affect the pathogenesis of AD and may lead to newer and better therapeutics for the prevention or treatment of AD.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 阿尔茨海默病（AD）是一种神经退行性疾病，发病机制复杂，治疗干预有限。 AD 的主要病理特征是 B-淀粉样蛋白 (AB) 肽的积累、tau 蛋白的过度磷酸化和神经元损伤。 AB 的积累可能特别重要，因为特定基因的突变（如家族性 AD 中发生的那样）与 AB 水平升高相关。 虽然这些基因突变导致家族性 AD 中 AB 的积累，但大多数 AD 病例中 AB 水平升高的致病因素尚不清楚。 高胆固醇血症和咖啡因是能够调节 AB 水平并可能影响 AD 发病机制的两个因素。 我们的长期目标是确定这些因素导致 AD 病理的风险和机制。 该提案的目的是确定富含胆固醇的饮食触发和咖啡因减轻或加剧兔脑中 AD 样病理的程度和机制。 该提案要测试的假设是 (1) 富含胆固醇的饮食会导致 B-淀粉样蛋白 (AB) 积累、tau 蛋白过度磷酸化和神经变性，涉及腺苷 A2A 受体 (A2AR)、肌醇 1,4,5-三磷酸受体 (IP3R) 和兰尼碱受体 (RyR) 的调节，以及 (2) 咖啡因诱导的 A2AR 阻断或通过 IP3R 阻断钙释放将减弱，而咖啡因诱导的 RyR 调节的钙通道释放钙将加剧 AB 积累、tau 过度磷酸化和神经变性。 我们的具体目标如下： 目标 1：确定饲喂富含胆固醇饮食的兔子大脑中 A2AR、RyR 和 IP3R 表达的改变程度；目标 2：确定咖啡因剂量依赖性调节兔脑中胆固醇诱导的 AD 样病理并调节 A2AR、RyR 和 IP3R 的程度；目标 3：确定 A2AR、RyR 和 IP3R 参与胆固醇诱导的 AB 积累、tau 磷酸化和氧化损伤的程度。 成功完成这里提出的工作将增加我们对胆固醇和咖啡因这两种因素影响 AD 发病机制的细胞机制的理解，并可能带来更新更好的 AD 预防或治疗疗法。