Captopril Enables the Inhibition of tRNA-Mediated Tau Aggregation

Abstract

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.