AGING AND ALZHEIMER AMYLOID PROTEIN CHEMISTRY

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This study is part of a multiphase project whose long term objective is to understand the formation of brain amyloid deposits and the role of Alzheimer precursor protein in the molecular pathology of Alzheimer's disease. The amyloid precursor protein is a cell membrane protein whose proteolytic processing leads to small amyloidigenic peptides called the beta-protein. Currently, we have little understanding of why some peptides form beta-sheets and aggregate into diffuse amorphous forms and others in fibrils. Recent reports indicate that the beta-protein can form either dense aggregates (pathological) or more diffuse deposits (non-pathological) depending on the local environment, i.e., cerebral vs. cerebellar. The physical properties of a model peptide system will be investigated using peptide analogs. The effect of different amino acid substitutions on the structure of amyloid as mimicked by synthetic peptide analogues will be monitored using EM, x-ray and NMR methodologies. We also will study the physical biochemistry of the synthetic amyloid in the presence of detergents and lipids. the NMR spectra of the peptides will be used to study the structure in solution with initial studies concentrating on the assignment of the various resonances of the histidine side chain atoms. We also will synthesis peptides with the 13C isotope incorporated into the His-13 residue. Binding assays and assays of the trophic effect of the peptide analogues will also be performed using a neuroblastoma cell culture system. The structural data derived from the above studies will be correlated with the changes in the binding of antibodies to the peptide analogues. This will allow for further definition of the epitope sites on the peptides.