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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 β-conformation and interact with other tau molecules. In the filament core, the microtubule-binding repeat region of tau has a cross-β structure, while the rest of the protein retains its largely unfolded structure and gives rise to the fuzzy coat of the filaments.