Thioredoxin-dependent redox homeostasis modulates tau-seeded aggregation in HEK293 TauRD biosensor cells.

Tau aggregation is a central pathological feature of Alzheimer's disease (AD) and other tauopathies. Although oxidative stress has been implicated in AD pathogenesis, the effects of intracellular redox perturbation on tau-seeded aggregation remain incompletely understood. In this study, we investigated the role of thiol redox homeostasis in tau-seeded aggregation using HEK293 TauRD fluorescence resonance energy transfer biosensor cells. Intracellular redox conditions were manipulated using the glutathione synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) and through overexpression or knockdown of thioredoxin (TXN), a key regulator of cellular thiol redox balance. BSO treatment significantly reduced intracellular glutathione levels without causing overt cytotoxicity, confirming successful redox alteration. However, BSO treatment failed to significantly alter tau-seeded aggregation. By contrast, TXN knockdown resulted in a modest but reproducible reduction in seeded aggregation efficiency without affecting total tau reporter expression. These findings indicate that acute glutathione depletion alone is insufficient to modulate tau-seeded aggregation in this cellular model. Furthermore, disruption of the TXN system inluences tau seeding in a manner that cannot be explained simply by increased oxidative stress. Together, our results suggest that thiol redox homeostasis contributes to the regulation of tau-seeded aggregation through mechanisms beyond a simple shift toward an oxidizing intracellular environment.