Alzheimer's disease (AD) and some other neurodegenerative diseases are characterized by a progressive accumulation of neurofibrillary tangles (NFT) and amyloid-rich senile plaques (SP). Although not restricted to AD, the number of SPs and NFTs correlates with the severity of dementia. The tangles are most probably formed from tau, a microtubule-associated protein, and other brain proteins, like neurofilaments (NFs). We identified a serine residue on human tau which, when phosphorylated, changes the normal protein to A68, a group of polypeptides that are AD- specific and present in NFTs. We also demonstrated that in certain circumstances, phosphorylation changes the conformation of synthetic peptides corresponding to human NF and tau from a helical-turn structure to beta-pleated sheets that are characteristic of the tangles at the electron microscopic level. Phosphorylation probably also plays a vital role in the function, transport, degradation, etc., of these and other neuronal cytoskeletal proteins. The phosphorylation sites of NF and tau are embedded in similar amino acid regions and have a high metal ion binding potential. We propose to synthesize non-phosphorylated and phosphorylated peptides corresponding to normal and abnormal phosphorylation sites of human tau protein. We will use circular dichroism (CD), nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopy to determine the conformation of the peptides in different solvents and environmental conditions. We are looking for phosphate acceptor sites that may serve as cores for intermolecular aggregate formation after abnormal post- translational modifications have changed the conformation. We also propose to extend these studies to those fragments of NF that abet the deposition of tau and thereby give rise to the known microscopic structure of NFTs. These studies will give insights into the topographical and environmental requirements for deposits of abnormal proteins in AD.