The REGγ-20S proteasome is an ubiquitin- and ATP-independent degradation system, targeting selective substrates, possibly helping to regulate aging. The studies we report here demonstrate that aging-associated REGγ decline predisposes to decreased tau turnover, as in a tauopathy. The REGγ proteasome promotes degradation of human and mouse tau, notably phosphorylated tau and toxic tau oligomers that shuttle between the cytoplasm and nuclei. REGγ-mediated proteasomal degradation of tau was validated in 3-12-month-old REGγ knockout (KO) mice, REGγ KO;PS19 mice, and PS19 mice with forebrain conditional neuron-specific overexpression of REGγ (REGγ OE) and behavioral abnormalities. Coupled with tau accumulation we found with REGγ-deficiency, neuron loss, dendrite reduction, tau filament accumulation, and microglial activation are much more prominent in the REGγ KO;PS19 than the PS19 model. Moreover, we observed that the degenerative neuronal lesions and aberrant behaviors were alleviated in REGγ OE;PS19 mice. Memory and other behavior analysis substantiate the role of REGγ in prevention of tauopathy-like symptoms. In addition, we investigated the potential mechanism underlying aging-related REGγ decline. This study provides valuable insights into the novel regulatory mechanisms and potential therapeutic targets for tau-related neurodegenerative diseases.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.