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.
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