Captopril Enables the Inhibition of tRNA-Mediated Tau Aggregation.

Tau is an intrinsically disordered protein critical to the nervous system, and its aberrant aggregation is a key pathogenic factor in multiple diseases. However, the underlying triggers remain elusive. Here, using in vitro reconstitution and high-resolution imaging, we identify tRNA as a major inducer of tau aberrant aggregation. Mechanistically, tRNA drives the formation of fibrillar aggregates from tau liquid-liquid phase separation (LLPS) condensates via electrostatic interactions, which over time can evolve into pathological aggregates. Moreover, captopril (CAP) effectively inhibits both general and tRNA-induced tau aggregation, positioning CAP as a potential therapeutic candidate. This work offers an avenue for treating aberrant phase separation-induced tau aggregation using small-molecule compounds.