The goal of the proposed research is to contribute to the elucidation of the molecular mechanism of Alzheimer's disease with a focus on the deficits observed in synaptic transmission, synaptic plasticity and memory and learning in a mouse model of Alzheimer's disease. The mouse model that will be used in the experiments is a mouse engineered to over expressing the human APP protein carrying mutations which are known to cause Alzheimer's disease in humans. We have demonstrated that these mice exhibit deficits in synaptic transmission, synaptic plasticity, and spatial learning. We will also examine the role of neurogenesis and exercise in Alzheimer's disease.
Aim 1 of this proposal is to examine the role of nicotinic receptors in Alzheimer's disease. Behavioral studies have linked the cholinergic system to learning and memory, which is intriguing given the observation that Alzheimer's patients have a deficiency in memory function and cortical nicotinic receptors. The first class of drugs approved for the treatment of Alzheimer's disease, which still today constitutes the best available treatment, are the cholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine), which boost cholinergic function.
Aim 1 of this proposal will be to test the hypothesis that binding of the beta-amyloid fragment (1-42) to the nicotinic receptor alpha 7 leads to the pathology seen in Alzheimer's disease. These experiments may either support or refute the idea that the cholinergic receptor system plays an important role in Alzheimer's disease. Either outcome will provide important information for developing strategies to prevent or reverse Alzheimer's disease.
Aim 2 of this proposal is to test the role of the APP C-terminal caspase cleavage site and its proteolytic products in Alzheimer's disease. We have shown that mice over expressing the mutant human APP protein that causes human Alzheimer's disease exhibit deficits in synaptic transmission, synaptic plasticity and spatial learning. On the other hand, mice expressing the same mutant APP protein but with a deletion of a caspase cleavage site near the APP protein c-terminal are protected from the deficits. These observations predict that APP cterminal proteolytic fragments are causing synaptic damage and this hypothesis will be tested directly.
Our genetic studies will test ideas about the involvement of neurotransmitter receptors, exercise, and neurogenesis in the mechanism of Alzheimer's disease. We will also test the hypothesis that proteolytic cleavage of the APP protein is an essential step in the development of Alzheimer's disease. The results and insights from these studies should make it possible to develop new targets for drug therapy to treat Alzheimers's disease.
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