Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, 351 Linus Pauling Science Center, Corvallis, OR, 97331, USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
Geroscience. 2023 Jun;45(3):1451-1469. doi: 10.1007/s11357-023-00760-2. Epub 2023 Mar 28.
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.
细胞衰老可能导致与年龄相关疾病（如阿尔茨海默病）相关的慢性炎症，其清除可预防神经tau 病模型中的认知障碍。Nrf2 是损伤反应途径和炎症调节剂的主要转录因子，随着年龄的增长而下降。我们之前的工作表明，沉默 Nrf2 会导致细胞和小鼠过早衰老。其他人已经表明，Nrf2 缺失会加剧一些 AD 模型的认知表型。在这项研究中，我们旨在通过在 Nrf2 敲除（Nrf2KO）背景下表达突变型人类 tau 转基因，来了解 Nrf2 消除、衰老和 AD 认知障碍之间的关系。我们评估了存在和不存在 Nrf2 时 P301S 小鼠的衰老细胞负担和认知下降。最后，我们用两种衰老治疗药物进行了为期 4.5 个月的治疗，以分析它们预防衰老细胞负担和认知下降的潜力：衰老溶解药物达沙替尼和槲皮素（DQ）和衰老形态药物雷帕霉素。Nrf2 缺失加速了 P301S 小鼠后肢瘫痪的发作。在 8.5 个月大时，P301S 小鼠没有表现出记忆缺陷，而没有 Nrf2 的 P301S 小鼠则明显受损。然而，我们检查的任何组织中 Nrf2 缺失都没有增加衰老标志物的表达。在 P301S 小鼠中，两种药物治疗都没有改善认知表现，也没有降低大脑中衰老标志物的表达。相反，雷帕霉素在使用的剂量下治疗会延迟空间学习，并导致空间记忆略有下降。总的来说，我们的数据表明，衰老的出现可能与 P301S 模型中认知下降的发生有关，表明 Nrf2 通过可能包括但不依赖于抑制衰老的机制来保护 AD 模型中的大脑功能，并表明 DQ 和雷帕霉素作为 AD 治疗的可能局限性。
