Cholesterol and Copper Affect Learning and Memory

描述（由申请人提供）：胆固醇和铜对营养和正常脑功能至关重要，但最近的证据也表明两者与阿尔茨海默病有关。胆固醇对细胞结构、修复和信号传导、激素产生和胆汁酸合成很重要，但也是动脉粥样硬化、冠心病和阿尔茨海默病的主要危险因素。高胆固醇饮食会导致淀粉样蛋白沉积——阿尔茨海默病的标志。铜对生长、心血管、内分泌和肺功能很重要，但铜的失衡与智力迟钝、贫血、中毒和阿尔茨海默病有关。铜参与β -淀粉样蛋白的代谢、聚集和毒性，在阿尔茨海默病患者的血液中似乎含量升高，并且是死后阿尔茨海默病患者大脑老年斑中发现的微量金属之一。我们已经确定，胆固醇和铜影响兔的经典条件下的硝化膜反应和心率。新的数据表明，胆固醇可以延缓对“旧”记忆的回忆——那些在高胆固醇饮食之前形成的记忆。当前更新的假设是基于胆固醇和β淀粉样蛋白影响学习和记忆，其机制是由胆固醇对中枢神经系统的直接和间接影响介导的。目前的提案以三个特定目标来验证这一假设，将重点放在胆固醇对获得新记忆的影响的细胞和分子机制上（特定目标1），并研究胆固醇对记忆保留的影响（特定目标2）。一旦我们了解了胆固醇对滞留的影响，我们将研究其细胞和分子机制（具体目标3）。这项工作很重要，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的理解产生影响。这项研究将具有相当重要的意义，因为它将明确胆固醇、铜和β淀粉样蛋白在学习和记忆中的作用，并通过将胆固醇喂养的兔子作为一种有价值的非转基因工具，推进该领域的研究，以寻找治疗和治愈阿尔茨海默病的方法。这项提议的工作是创新的，因为它结合了兔核磁共振的经典条件反射——一种被很好地理解的学习和记忆的行为和神经模型——和简单的饮食操纵，即喂食胆固醇来检查胆固醇和β淀粉样蛋白的影响——两种阿尔茨海默病的“确凿证据”。公共卫生相关性：胆固醇是心血管疾病的主要危险因素，现在有证据表明胆固醇是阿尔茨海默病的主要危险因素。因此，高胆固醇似乎是美国两种最普遍疾病的主要因素。90年来，喂食胆固醇的兔子一直是心血管疾病的主要模型，最近的研究显示，它的大脑中积累了-淀粉样蛋白。因此，给兔子喂食胆固醇将会成为一个很好的非转基因阿尔茨海默病模型。此外，降低胆固醇水平可能是一种减少-淀粉样蛋白积累的可行方法，就像治疗心脏病一样。

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. PUBLIC HEALTH RELEVANCE: Cholesterol is a major risk factor for cardiovascular disease and there is now evidence that cholesterol is a major risk factor for Alzheimer's disease. Consequently, high cholesterol appears to be the major factor in two of the most widespread diseases in the US. The cholesterol-fed rabbit has been the primary model for cardiovascular disease for 90 years and has recently been shown to accumulate beta amyloid in the brain. Thus, feeding a rabbit cholesterol would make a good non-transgenic model of Alzheimer's disease. Moreover, reducing cholesterol levels may be as viable a means of reducing beta amyloid accumulation as it is in treating heart disease.