Tet-On: An Inducible System for Studying Pathological Tau Dynamics

Tauopathies, including Alzheimer’s disease and frontotemporal dementia, are characterized by abnormal post-translational modification, misfolding, and aggregation of the microtubule-associated protein tau, resulting in neuronal dysfunction and degeneration. To model early, human-specific mechanisms of tau pathology, we generated an inducible human induced pluripotent stem cell (iPSC) line expressing the 0N4R tau isoform with the P301L mutation. A doxycycline-responsive Tet-On system driving mClover3-tagged tau enables precise temporal control of expression in both proliferative and differentiated states, including cortical organoids. This platform will facilitate mechanistic studies of tau synthesis, aggregation dynamics, and downstream cellular responses, and provides a scalable system for developing therapeutic interventions.