Cholesterol and Copper Affect Learning and Memory

描述(申请人提供)：胆固醇和铜对营养和正常的大脑功能至关重要，但最近的证据也表明这两者都与阿尔茨海默病有关。胆固醇对细胞结构、修复和信号传递、激素产生和胆汁酸合成都很重要，但也是动脉粥样硬化、冠心病和阿尔茨海默病的主要风险因素。高胆固醇饮食会导致β淀粉样蛋白沉积--这是阿尔茨海默病的一个特征。铜对生长、心血管、内分泌和肺功能都很重要，但铜失衡与智力低下、贫血、中毒和阿尔茨海默病有关。铜参与β淀粉样代谢、聚集、毒性，在阿尔茨海默氏症患者的血液中似乎升高，是死后阿尔茨海默氏症大脑老年斑中发现的痕量金属之一。我们已经证实，胆固醇和铜影响兔瞬膜反应和心率的经典条件反射。新的数据表明，胆固醇会延缓人们对“旧”记忆的回忆--那些在高胆固醇饮食之前形成的记忆。目前更新所基于的假设是，胆固醇和β淀粉样蛋白影响学习和记忆，相关机制是通过胆固醇对中枢神经系统的直接和间接影响而介导的。目前的提案用三个特定目标来检验这一假说，重点是研究胆固醇对新记忆获得的潜在细胞和分子机制(特定目标1)，并调查胆固醇对记忆保持的影响(特定目标2)。一旦我们了解了胆固醇对滞留的影响，我们将研究它的细胞和分子机制(具体目标3)。这项工作之所以重要，是因为它将对理解膳食胆固醇和β淀粉样蛋白沉积在学习和记忆中的作用以及我们对学习和记忆失败的发病机制产生影响。这项研究将具有相当重要的意义，因为它将确立胆固醇、铜和β淀粉样蛋白在学习和记忆中的明确作用，并通过增加胆固醇喂养的兔子作为一种有价值的非转基因工具来探索阿尔茨海默病的治疗和治愈，从而推动该领域的发展。这项拟议的工作具有创新性，因为它结合了对兔子核磁共振的经典条件作用--一种众所周知的学习和记忆的行为和神经模型--与喂食胆固醇的简单饮食操作相结合，以检查胆固醇和β淀粉样蛋白的影响--这两种物质是阿尔茨海默氏症的两个“确凿证据”。

DESCRIPTION (provided by applicant): Cholesterol and copper are crucial to nutrition and normal brain function but recent evidence also implicates both in Alzheimer's disease. Cholesterol is important for cell structure, repair and signaling, hormone production and bile acid synthesis but is also a major risk factor for atherosclerosis, coronary heart disease, and Alzheimer's disease. A high-cholesterol diet can result in beta amyloid deposits - a hallmark of Alzheimer's disease. Copper is important for growth, cardiovascular, endocrine and pulmonary function but copper imbalance has been linked to mental retardation, anemia, toxicosis and Alzheimer's disease. Copper is involved in beta amyloid metabolism, aggregation, toxicity, appears to be elevated in the blood of Alzheimer's patients, and is one of the trace metals found in senile plaques of post-mortem Alzheimer's brains. We have established that cholesterol and copper affect classical conditioning of the rabbit nictitating membrane response and heart rate. New data suggest cholesterol can retard the recall of "old" memories - those formed before a high cholesterol diet. The hypothesis on which the current renewal is based is that cholesterol and beta amyloid affect learning and memory and that the mechanism involved is mediated by direct and indirect effects of cholesterol on the CNS. The current proposal tests this hypothesis with three specific aims will focus on cellular and molecular mechanisms underlying cholesterol effects on acquisition of new memories (Specific Aim 1) and investigate the effects of cholesterol on memory retention (Specific Aim 2). Once we understand the effects of cholesterol on retention we will then examine its cellular and molecular mechanisms (Specific Aim 3). This work is important because of the impact it will have on understanding the role of dietary cholesterol and beta amyloid deposits in learning and memory and on our understanding of the pathogenesis of failures in learning and memory. The research will be of considerable significance because it will establish a clear role for cholesterol, copper and beta amyloid in learning and memory and advance the field by adding the cholesterol-fed rabbit as a valuable non-transgenic tool to the search for treatments of and a cure for Alzheimer's disease. The proposed work is innovative because it combines classical conditioning of the rabbit NMR - a well- understood behavioral and neural model of learning and memory - with the simple dietary manipulation of feeding cholesterol to examine the effects of cholesterol and beta amyloid - two of the "smoking guns" of Alzheimer's disease.