The applicants have discovered an entirely new and powerful method of polymerizing tau protein into filaments resembling the straight filaments found in the neurofibrillary pathology of Alzheimer's disease. The inducing agents are membrane phospholipids and fatty acids that are known to function as signal transduction molecules in vivo. The resultant filaments are regular, and available in large quantities. By analyzing the structure and genesis of these filaments, they will address important questions regarding tau filament formation and neurodegenerative disease. Which membrane-associated components are capable of stimulating tau self-association and polymerization? Does the resultant structure-activity-relationship point toward the involvement of known signal transduction mechanisms in filament biogenesis? What is the role of phosphorylation on tau self-assembly and intracellular stability? Four Aims are proposed to address these questions. 1) The process of tau filament formation will be quantified. Using a novel assembly assay, they will quantify the rate, extent, and ligand dependence of tau filament formation in vitro. 2) The structural features on tau required for filament formation will be determined. These studies will clarify the structural requirements of tau polymerization and the location of a ligand-binding site potentially useful for development of high-affinity agents for therapeutic and diagnostic applications. 3) The influence of post-translational modification on tau polymerization kinetics will be assessed. These studies will clarify the impact of phosphorylation and glycation on tau filament formation. 4) The effects of polymerization on tau structure will be determined. Using a combination of circular dichroism spectropolarimetry and hydrodynamic measurements, it will be determined whether tau adopts a defined structure upon filament formation. The results will have important implications for the feasibility of developing therapeutic agents capable of preventing, and premortem diagnostic agents capable of detecting, the formation of fibrillar pathology.
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