Physiologic Relevance of ApoE Association with A

ApoE is a protein that has been shown to be present in senile plaques and neurofibrillary tangles in the brains of patients with Alzheimer’s disease. There are three forms of this protein in the human population, referred to as apoE4, apoE3, and apoE2. Genetic studies have shown that individuals with one or two copies of the gene for the apoE4 form of the protein have increased risk for the development of sporadic and inherited late onset Alzheimer’s disease while individuals with the gene coding for the apoE2 form of the protein appear to have an increased protection against the development of the disease. ApoE3, but not apoE4, is able to protect cells against cell death mediated by the amyloidogenic Aß peptide, the major protein found in senile plaques and to bind to Aß. In addition, apoE3 is capable of promoting the growth of neurites on neurons. Once again, this property is not shared with apoE4. Neurite outgrowth would involve the rearrangement of proteins that maintain the shape of cells, the so called cytoskeletal proteins. ApoE3 but not apoE4 is able to bind to several of these proteins as well. These observations suggest that apoE may have a role in normal neuronal development and the development or prevention of Alzheimer’s disease. An understanding of how the different forms of apoE promote or prevent the development of Alzheimer’s disease may lead to important insights into the mechanism responsible for the changes that occur in the brains of Alzheimer’s patients. In this proposal we plan to determine which regions of the apoE3 protein are involved in protecting neurons from cell death mediated by Aß and promoting neurite extension. We will then examine if the same domains are involved in both high and low affinity binding to Aß and to cytoskeletal proteins. This will allow us to determine if the physiological role of apoE in these processes are mediated by its association with these proteins. These results may ultimately lead to the development of more useful mouse models of Alzheimer’s disease and the development of therapeutic peptides of apoE that may slow the progression or development of Alzheimer’s disease.