Tau, a major microtubule-associated protein in brain, forms abnormal fibers in Alzheimer's disease and several other neurodegenerative diseases. Tau is highly soluble and adopts a natively unfolded structure in solution. In the paired helical filaments of Alzheimer's disease, small segments of tau adopt a beta-conformation and interact with other tau molecules. In the filament core, the microtubule-binding repeat region of tau has a cross-beta structure, while the rest of the protein retains its largely unfolded structure and gives rise to the fuzzy coat of the filaments.