Tau catalyzes amyloid-β aggregation in a fold-dependent manner
Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases, yet the molecular mechanisms remain poorly understood. In Alzheimers disease (AD) and chronic traumatic encephalopathy (CTE), co-deposition of tau and amyloid-{beta} (A{beta}) leads to accelerated disease progression. Here, we investigated the direct interaction between A{beta} and tau, combining in vitro reconstruction, computational modeling, and in vivo models. We show that tau aggregates with AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of A{beta}42 in a fold-specific manner, through an enzyme-like kinetic with recognition mechanisms. CTE fibrils exhibit the highest catalytic activity, also constraining A{beta}42 polymorphism. PHF and CTE tau fibrils increase A{beta}42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans. Catalytic heterotypic interactions between amyloidogenic proteins offer new insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here may guide the structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.