Interactions with tau’s microtubule-binding repeats modulate amyloid-β aggregation and toxicity

Abstract

The complicated pathogenesis of Alzheimer's disease (AD) is characterized by the accumulation of neurofibrillary tangles and senile plaques, primarily composed of tau and amyloid-beta (A beta) aggregates, respectively. While substantial efforts have focused on unraveling the individual roles of tau and A beta in AD development, the intricate interplay between these components remains elusive. Here we report how the microtubule-binding repeats of tau engage with A beta in a distinct manner. Crucially, this interaction notably modifies A beta aggregation behavior, thereby altering A beta-associated toxicity within both extracellular and intracellular milieus. Our mechanistic investigations at the molecular level manifest specific fragments within tau's microtubule-binding domain that possess a balance of hydrophobic and hydrophilic properties, promoting the formation of hetero-adducts with A beta peptides. These findings offer avenues for understanding and treating AD by emphasizing the tau-A beta interplay in the pathogenesis.