Mechanism of core-tau unit assembly and inhibition in Alzheimer’s disease

The tau protein (residues 297-391) forms the core of oligomers and filaments that drive neurodegeneration in Alzheimer’s disease (AD). The mechanisms of pathological assembly and pharmacological inhibition need to be understood before novel treatments can be developed. Molecular dynamics modeling, confirmed by immunochemistry, revealed that self-assembly involves initial capture via residues 337-355 and a conformational switch at proline 332, followed by unfolding and zipper-like assembly into a stable H-bonded structure that occludes epitopes within the core domain. Hydromethylthionine (HMT), a clinically active tau aggregation inhibitor (TAI), works by stabilizing the core monomer in a wrapped-up conformation, which prevents its assembly. A pharmacophore model based on the HMT cryptic pocket was used to design novel active TAIs. These discoveries provide a basis for the rational design of new TAIs for the treatment of AD.