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: 7959949
• 负责人: OTHMAN GHRIBI
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959949
• 关键词: Adenosine A2A Receptor; Affect; Alzheimer' s Disease; Amyloid; Attenuated; Brain; Caffeine; Calcium; Calcium Channel; Cholesterol; Complex; Computer Retrieval of Information on Scientific Projects Database; Diet; Dose; Funding; Gene Mutation; Genes; Grant; ITPR1 gene; Inositol; Institution; Lead; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oryctolagus cuniculus; Pathogenesis; Pathology; Prevention; Research; Research Personnel; Resources; Risk; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Work; amyloid peptide; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病（AD）是一种神经退行性疾病，具有复杂的发病机制，治疗干预有限。 AD的主要病理标志是B-淀粉样蛋白（AB）肽的积聚、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中发生的突变，与AB水平升高相关。 虽然这些基因突变是导致家族性AD中AB积累的原因，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水平的两个因素，并可能影响AD的发病机制。 我们的长期目标是确定风险和机制，这些因素有助于AD的病理。 本提案的目的是确定高胆固醇饮食触发和咖啡因减弱或加重兔脑AD样病理的程度和机制。 在该提议中待检验的假设是（1）富含胆固醇的饮食引起B-淀粉样蛋白（AB）积累、tau过度磷酸化和涉及腺苷A2 A受体（A2 AR）、肌醇-1，4，5-三磷酸受体（IP 3R）和兰尼碱受体（RyR）调节的神经变性，和（2）咖啡因诱导的A2 AR阻断或通过IP 3R的钙释放阻断将减弱并且咖啡因诱导的钙从RyR调节的钙通道的释放将加剧AB积累，tau过度磷酸化和神经变性。 我们的具体目的如下：目的1：确定A2 AR、RyR和IP 3R的表达在喂食富含胆固醇的饮食的兔脑中改变的程度;目的2：确定咖啡因剂量依赖性地调节胆固醇诱导的AD样病理和调节兔脑中A2 AR、RyR和IP 3R的程度;以及目的3：确定A2 AR、RyR和IP 3R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两个因素（胆固醇和咖啡因）影响AD发病机制的细胞机制的理解，并可能导致预防或治疗AD的更新和更好的治疗方法。