Differential binding dynamics of four microtubule-binding repeats of tau with an amyloid-β fibril seed.

Abstract

Both senile plaques formed by amyloid-beta (Aβ) and neurofibrillary tangles comprised of tau are hallmarks of Alzheimer's disease (AD). The accumulation of neurofibrillary tangles better correlates with the loss of cognitive function than senile plaques, but neurofibrillary tangles 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 poorly understood. Herein, we 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 lateral instead of elongation surfaces of the fibril, preserving similar secondary structures as in the solution. In contrast, R2 and R4 had higher binding propensities to the elongation than lateral surfaces, adopting β-sheet structures by forming hydrogen bonds with the exposed hydrogen bond donors and acceptors. Together, our results suggest that four MTBD repeats play distinct roles in driving the binding of tau to two different surfaces of an Aβ fibril seed. The binding of tau to the lateral surface of Aβ fibril can increase the local concentration, while the binding in the elongation surface promotes β-sheet formation, both of which reduce the free energy barrier for tau aggregation nucleation and subsequent fibrillization. Our computational study offers molecular insight into the experimentally observed cross-seeding of Tau aggregation by pre-formed Aβ fibril seeds and helps better understand the pathological synergy of Aβ and tau aggregation in the etiology of AD.