Abstract
Both senile plaques formed by amyloid-β (Aβ) and neurofibrillary tangles (NFTs) comprised of tau are pathological hallmarks of Alzheimer's disease (AD). The accumulation of NFTs better correlates with the loss of cognitive function than senile plaques, but NFTs are rarely observed without the presence of senile plaques. Hence, cross-seeding of tau by preformed Aβ amyloid fibril seeds has been proposed to drive the aggregation of tau and exacerbate AD progression, but the molecular mechanism remains unknown. Here, we first identified cross-interaction hotspots between Aβ and tau using atomistic discrete molecular dynamics simulations (DMD) and confirmed the critical role of the four microtubule-binding repeats of tau (R1-R4) in the cross-interaction with Aβ. We further investigated the binding structure and dynamics of each tau repeat with a preformed Aβ fibril seed. Specifically, R1 and R3 preferred to bind the Aβ fibril lateral surface instead of the elongation end. In contrast, R2 and R4 had higher binding propensities to the fibril elongation end than the lateral surface, enhancing β-sheet content by forming hydrogen bonds with the exposed hydrogen bond donors and acceptors. Together, our results suggest that the four repeats play distinct roles in driving the binding of tau to different surfaces of an Aβ fibril seed. Binding of tau to the lateral surface of Aβ fibril can increase the local concentration, while the binding to the elongation surface promotes β-sheet formation, both of which reduce the free energy barrier for tau aggregation nucleation and subsequent fibrillization.