Coupling the Coupling: Dissecting the Role of Tau’s Microtubule-Binding Repeats in Modulating Amyloid-beta Aggregation and Toxicity Profiles in Alzheimer’s Disease

The accumulation of neurofibrillary tangles and senile plaques composed of tau and amyloid-beta (Abeta) aggregates, respectively, is observed in the brain of Alzheimer’s disease (AD). Efforts have been made to elucidate the link between the aggregation of tau and Abeta and the development of AD; however, the pathological implication of their co-aggregation remains unclear. Here we report that the microtubule-binding domain of tau, critical for its aggregation, has direct contacts onto Abeta and alters the aggregation behavior of Abeta in a distinct manner, which in turn affects the Ab-associated toxicity under both extracellular and intracellular conditions. Our mechanistic investigations illuminate that the fragments with the balanced hydrophobicity and hydrophilicity properties in the microtubule-binding domain of tau can form adducts with monomeric and dimeric Abeta to varying degrees, which may determine their impact on the aggregation and toxicity of Ab. These findings offer new avenues for understanding and treating AD by highlighting the interplay between tau and Abeta in the pathogenesis.