CONFORMATIONS OF ALZHEIMER PHF/TAU AND TAU PEPTIDES

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Two hallmark lesions present in brains of Alzheimer's diseased patients are senile plaques (SP) and neurofibrillay tangles (NFT). The NFT are composed of paired helical filaments (PHF) single straight filaments (SSF) and their density in AD brain sections has been correlated with the severity of the disease. Although NFT are the most visible abnormal structures occurring in AD at the cellular level, their formation, persistence and eventual neurotoxicity is most likely elicited by more subtle abnormal metabolic changes, ultimately directed by the cell genome. It follows that an understanding to those factors responsible for initiation of their formation and, in the case of NFT, their insolubility and protease resistance might provide clues to the underlying etiology of AD. The central goal of this proposal is to investigate some of the factors which have been postulated to initiate PHF formation and to maintain its structure. Numerous biochemical and immunological studies over the last decade have shown that PHF is composed of the microtubule associated protein, tau (PHF-tau). One of the primary differences between normal tau and PHF- tau is that PHF-tau appears to be more highly phosphorylated by ser/thr- pro directed kinases. Since phosphorylated tau shows decreased binding to microtubules, a reasonable hypothesis for the PHF assembly is an initial phosphorylation of tau which in turn leads to self-association of the protein monomers into fibers. One of the goals of this proposal is to determine if phosphorylation can indeed induce conformational changes in peptides homologous to sequences of tau known to be of importance in microtubule binding. Recently it has been found that non-phosphorylated full length tau is able to form PHF-like filaments under physiological conditions when incubated in vitro in the presence of glycosaminoglycans such as heparin and heparin sulfate. Furthermore, single fillaments can be formed when an 18-amino acid peptide derived from the microtubule binding region of tau is incubated with heparin or poly-L-glutamic acid. Using biophysical methods we intend to study conformational changes in this peptide and homologous peptides brought about under fiber inducing conditions. This will address the hypothesis of whether a conformational change is a preliminary condition to fiber formation. A detailed model of any conformational changes will be derived from CD and NMR/distance geometry methods.