AGING AND ALZHEIMER DEMENTIA--ROLE OF FIBROUS PROTEINS

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DESCRIPTION: (adapted from Applicant's Abstract) Alzheimer's disease (AD) is characterized by the progressive accumulation of abnormal filaments, referred to as paired helical filaments (PHF), within neuronal perikarya and cell processes, in the form of neurofibrillary tangles (NFT), neuropil threads and dystrophic neurites in senile plaques. Paired helical filaments and biochemically similar 15-18 nm diameter straight filaments are composed of microtubule associated protein tau. Biochemical studies have shown that some PHF are soluble in sodium dodecyl sulfate (SDS) while other are insoluble, but the basis of significance of PHF heterogeneity is currently unknown. The tau protein in PHF (PHF-tau) differs from normal tau in phosphate content, isoelectric charge, number of and molecular weights of isoforms and solubility. Moreover, a pool of abnormal tau protein that is not associated with PHF, but has properties similar to PHF-tau, has been demonstrated in AD. The best characterized of the differences between PHF-tau and normal tau is extent and sites of phosphorylation. In addition to phosphorylation, PHF-tau differs from normal tau in its increased content of D-aspartate and decreased content of lysine residues. These observations are of interest in that racemization is increased in long-lived proteins and a particular type of modification of lysine groups in long-lived proteins, namely nonenzymatic glycation, has recently been suggested to play a role in PHF formation. Further studies of these properties may shed light on the mechanism of formation and stabilization into abnormal filaments. The specific goals of this proposal are to determine if post-translational modifications, such as glycation and racemization, are involved in PHF formation, aggregation and stabilization into the abnormal filaments that make up NFT, neuropil threads and dystrophic neurites in senile plaques. Six lines of investigation will be carried out. They include (1) comparison of the extent of glycation of SDS- soluble PHF, SDS-insoluble PHF, no-PHF- abnormal tau and cytosolic tau (equivalent to normal tau), (2) determination of the sites of glycation in tau and PHF differing in solubility, (3) comparison of AGE immunoreactivity in NFT with respect to condensation or coalescence of filaments (4) comparison of he susceptibility of different forms of tau to glycation, (5) determination of the effect of glycation on tau-tubulin, and tau-tau interactions, and (6) determination of the effect of racemization (D-aspartate) on the function of tau, and the distribution and the content of D-aspartate in PHF-tau and non- PHF abnormal tau.