Alzheimer's Amyloid-β Accelerates Cell Senescence and Suppresses the SIRT1/NRF2 Pathway in Human Microglial Cells

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-β (Aβ) accelerated cell senescence characterized by the upregulation of p21 and PAI-1 as well as senescence-associated beta-galactosidase (SA-β-gal) in human microglial cells. Consistently, Aβ 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, Aβ 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 Aβ. In summary, our findings revealed that Aβ 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.