Coaggregation with Aβ Drives β-Sheet Formation in tau Microtubule-Binding Repeats.

Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles formed by amyloid-β (Aβ) and tau aggregates, yet the molecular basis of Aβ-tau coaggregation remains unclear. Here, we used multiple microsecond-scale discrete molecular dynamics simulations to examine homodimerization of tau microtubule-binding repeats (R1-R4) and their heterodimerization with Aβ. R1, R2, and R4 showed weak homodimerization, whereas heterodimerization with Aβ markedly enhanced interpeptide contacts and β-sheet formation. R3 exhibited strong intrinsic aggregation propensity and was further stabilized into β-sheet-rich conformations upon interacting with Aβ. Residue-level analyses identified Aβ11-21 and Aβ30-41 as structural templates promoting β-sheet transitions in tau. Thermodynamic analyses further supported an energy-entropy compensation mechanism in which aggregation-prone β-sheet edges of Aβ lowered the potential energy to offset entropic costs, thereby stabilizing low-free-energy coaggregated states. These findings provide atomistic insights into Aβ-facilitated tau coaggregation relevant to early AD pathology.