Effect of Nrf2 loss on senescence and cognition of tau-based P301S mice

Abstract

Cellular senescence may contribute to chronic inflammation involved in the progression of age-related diseases such as Alzheimer's disease (AD), and its removal prevents cognitive impairment in a model of tauopathy. Nrf2, the major transcription factor for damage response pathways and regulators of inflammation, declines with age. Our previous work showed that silencing Nrf2 gives rise to premature senescence in cells and mice. Others have shown that Nrf2 ablation can exacerbate cognitive phenotypes of some AD models. In this study, we aimed to understand the relationship between Nrf2 elimination, senescence, and cognitive impairment in AD, by generating a mouse model expressing a mutant human tau transgene in an Nrf2 knockout (Nrf2KO) background. We assessed senescent cell burden and cognitive decline of P301S mice in the presence and absence of Nrf2. Lastly, we administered 4.5-month-long treatments with two senotherapeutic drugs to analyze their potential to prevent senescent cell burden and cognitive decline: the senolytic drugs dasatinib and quercetin (DQ) and the senomorphic drug rapamycin. Nrf2 loss accelerated the onset of hind-limb paralysis in P301S mice. At 8.5 months of age, P301S mice did not exhibit memory deficits, while P301S mice without Nrf2 were significantly impaired. However, markers of senescence were not elevated by Nrf2 ablation in any of tissues that we examined. Neither drug treatment improved cognitive performance, nor did it reduce expression of senescence markers in brains of P301S mice. Contrarily, rapamycin treatment at the doses used delayed spatial learning and led to a modest decrease in spatial memory. Taken together, our data suggests that the emergence of senescence may be causally associated with onset of cognitive decline in the P301S model, indicate that Nrf2 protects brain function in a model of AD through mechanisms that may include, but do not require the inhibition of senescence, and suggest possible limitations for DQ and rapamycin as therapies for AD.

Keywords: Ageing; Alzheimer’s disease; DQ; Nrf2; Rapamycin; Tauopathy.