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

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-β (Aβ) aggregates, respectively. While substantial efforts have focused on unraveling the individual roles of tau and Aβ in AD development, the intricate interplay between these components remains elusive. Here we report how the microtubule-binding repeats of tau engage with Aβ in a distinct manner. Crucially, this interaction notably modifies Aβ aggregation behavior, thereby altering Aβ-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 Aβ peptides. These findings offer avenues for understanding and treating AD by emphasizing the tau-Aβ interplay in the pathogenesis.