In this study, we identified Usp7 and Usp10 as two deubiquitinating enzymes (DUBs) whose downregulation or pharmacological inhibition robustly reduced seeded TAU aggregation in both cortical (CTX) and organotypic hippocampal slice cultures (OHSCs) derived from rTg4510 mice, as well as in wildtype CTX seeded with Alzheimer’s disease (AD)-derived pathological TAU. The gene discussed is USP7; the disease is Alzheimer disease.