Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner.

Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer's disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.