Cholesterol and copper affect learning and memory

描述(申请人提供)：尽管胆固醇和铜在营养和正常的大脑功能中扮演着关键的角色，但它们都是阿尔茨海默病的病因中的重要因素。高胆固醇饮食已被证明会导致β淀粉样蛋白沉积--这是阿尔茨海默病的特征之一。铜参与β淀粉样代谢，似乎在阿尔茨海默病患者的血液中升高，并在阿尔茨海默病患者死后大脑的老年斑中发现。目前尚不清楚胆固醇和铜是如何影响学习和记忆的，但很明显，它们与阿尔茨海默氏症有关，阿尔茨海默病的特征是严重的学习和记忆缺陷。超过1亿美国成年人的血液总胆固醇水平高于200毫克/分升，其中4100万人的总胆固醇水平高于240毫克/分升，了解胆固醇对记忆力和阿尔茨海默氏症的影响可能会对美国公共健康产生重大影响。美国饮用水中不同浓度的铜及其在阿尔茨海默病中的作用表明，了解铜、胆固醇和β淀粉样蛋白之间的相互作用也可能对美国公共健康产生重大影响。这项建议的目的是利用经典的兔瞬膜条件反射和心率反应来确定胆固醇和铜对学习和记忆的影响。中心假设是，高胆固醇饮食和β淀粉样蛋白的沉积会影响学习和记忆。这一假说是基于我们的初步发现，即胆固醇可以促进或严重阻碍学习和记忆，这取决于沉积在大脑中的β淀粉样蛋白的水平和性质。我们已经发现，只需在饮用水中添加微量铜(0.12 ppm)，胆固醇诱导的β淀粉样沉积就会变成老年斑样结构，并延缓学习。提出这项研究的理由是：(1)胆固醇和铜在正常大脑功能中的作用，(2)通过简单的饮食操作提高胆固醇和向水中添加铜的能力，从而诱导β-淀粉样蛋白沉积和斑块，(3)β-淀粉样蛋白在阿尔茨海默病中的作用，(4)人和兔的β-淀粉样蛋白的序列同一性，以及(5)对兔学习和记忆的行为和底物的良好理解--兔将成为研究胆固醇和β-淀粉样蛋白沉积对学习和记忆的影响的理想动物模型，因此，一种潜在的阿尔茨海默病动物模型。有了这样的模型，我们或许能够帮助理解β淀粉样蛋白在学习和记忆中的作用，并开发治疗阿尔茨海默病的新的创新方法。

DESCRIPTION (provided by applicant): Despite the crucial role played by cholesterol and copper in nutrition and normal brain function, they are both important factors in the etiology of Alzheimer's disease. A high cholesterol diet has been shown to result in beta amyloid deposits - one the hallmarks of Alzheimer's disease. Copper is involved in beta amyloid metabolism, appears to be elevated in the blood of Alzheimer's patients and has been found in the senile plaques of Alzheimer's brains post-mortem. It is not yet clear how cholesterol and copper affect learning and memory but it is clear that they are involved in Alzheimer's disease, which is characterized by profound deficits in learning and memory. With over 100 million American adults having total blood cholesterol levels higher than 200 mg/dL, and of those, 41 million having levels higher than 240 mg/dL, understanding the effects of cholesterol on memory and Alzheimer's disease could have a large impact on US public health. The presence of copper in the US drinking water at varying concentrations and its role in Alzheimer's disease suggest that understanding the interplay between copper, cholesterol, and beta amyloid could also have a significant impact on US public health. The objective of this proposal is to determine the effects of cholesterol and copper on learning and memory using classical conditioning of the rabbit nictitating membrane and heart rate response. The central hypothesis is that a high-cholesterol diet and deposits of beta amyloid affect learning and memory. This hypothesis is based on our preliminary findings that cholesterol can facilitate or severely retard learning and memory depending on the level and the nature of the beta amyloid deposited in the brain. We have found that cholesterol-induced beta amyloid deposits can become senile plaque-like structures and retard learning simply by adding trace amounts of copper (0.12 PPM) to the drinking water. The rationale for the proposed research is that given (1) the role of cholesterol and copper in normal brain function, (2) the ability to elevate cholesterol and add copper to the water with a simple dietary manipulation and thereby induce beta amyloid deposits and plaques, (3) the role of beta amyloid in Alzheimer's disease, (4) the sequence identity of human and rabbit beta amyloid, and (5) a good understanding of the behavior and substrates of learning and memory in the rabbit - the rabbit would make an ideal animal model for studying the effects of cholesterol and beta amyloid deposits on learning and memory, and thus, a potential animal model of Alzheimer's disease. With such a model, we may be able to help understand the role of beta amyloid in learning and memory and develop new and innovative approaches to the treatment of Alzheimer's disease.