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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病(AD)是一种具有复杂发病机制的神经退行性疾病，其治疗干预措施有限。阿尔茨海默病的主要病理特征是B-淀粉样蛋白积聚、tau蛋白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，如在家族性AD中发生的，与AB水平的升高有关。虽然这些基因突变是家族性AD中AB积聚的原因，但在大多数AD病例中AB水平升高的原因尚不清楚。高胆固醇血症和咖啡因是调节AB水平的两个因素，可能影响AD的发病机制。我们的长期目标是确定这些因素在AD病理中的风险和机制。这项建议的目的是确定高胆固醇饮食触发和咖啡因减轻或加重兔脑内AD样病理的程度和机制。这项建议要检验的假设是：(1)高胆固醇饮食导致B-淀粉样蛋白(AB)堆积、tau过度磷酸化和神经变性，涉及腺苷A2a受体(A2AR)、三磷酸肌醇-1，4，5-肌醇(IP3R)和兰诺定受体(RyR)的调节，以及(2)咖啡因诱导的A2AR阻断或通过IP3R阻断钙释放将减弱咖啡因诱导的RyR调节的钙通道的钙释放将加剧AB的积累、tau过度磷酸化和神经变性。我们的具体目标如下：目的1：确定喂饲高胆固醇饮食的兔脑内A2AR、RyR和IP3R表达的变化程度；目的2：确定咖啡因剂量依赖地调节胆固醇诱导的AD样病理并调节A2AR、RyR和IP3R在兔脑中的程度；以及目标3：确定A2AR、RyR和IP3R在胆固醇诱导的AB堆积、tau磷酸化和氧化损伤中的参与程度。这项工作的成功完成将增加我们对胆固醇和咖啡因这两个因素影响AD发病机制的细胞机制的理解，并可能导致更新和更好的治疗方法来预防或治疗AD。

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.