State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Oxid Med Cell Longev. 2022 Aug 17;2022:3086010. doi: 10.1155/2022/3086010. eCollection 2022.
Microglia play important roles in maintenance of brain homeostasis, while due to some pathological stimuli in aging-related neurodegenerative diseases including Alzheimer's disease, they are malfunctioning. Here, we demonstrated that amyloid- (A) accelerated cell senescence characterized by the upregulation of p21 and PAI-1 as well as senescence-associated beta-galactosidase (SA--gal) in human microglial cells. Consistently, A induced the senescence-associated mitochondrial dysfunctions such as repression of ATP production, oxygen consumption rate (OCR), and mitochondrial membrane potential and enhancement of ROS production. Furthermore, A was found to significantly suppress mRNA expression and protein level of Sirtuin-1 (SIRT1), a key regulator of senescence, and inhibit mRNA expression and translocation of NRF2, a critical transcription factor in inflammatory responses, leading to impairment of phagocytosis. Rescue of SIRT1, as expected, could counteract the pathological effects of A. In summary, our findings revealed that A accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of SIRT1 may provide a potential alternative treatment.
小胶质细胞在维持大脑内环境稳定方面发挥着重要作用，但由于衰老相关神经退行性疾病（包括阿尔茨海默病）中的一些病理刺激，它们会出现功能障碍。在这里，我们证明了淀粉样蛋白（A）可加速细胞衰老，其特征是 p21 和 PAI-1 以及衰老相关β-半乳糖苷酶（SA-β-gal）的上调。一致地，A 诱导了与衰老相关的线粒体功能障碍，例如抑制 ATP 产生、耗氧率（OCR）和线粒体膜电位，并增强 ROS 产生。此外，发现 A 可显著抑制 Sirtuin-1（SIRT1）的 mRNA 表达和蛋白水平，SIRT1 是衰老的关键调节剂，并抑制核因子红细胞 2（NRF2）的 mRNA 表达和易位，NRF2 是炎症反应中的关键转录因子，导致吞噬作用受损。如预期的那样，SIRT1 的挽救可以逆转 A 的病理作用。总之，我们的研究结果表明，A 主要通过抑制 SIRT1/NRF2 通路加速人小胶质细胞衰老，并表明 SIRT1 的遗传和药物挽救可能提供一种潜在的替代治疗方法。
