AUTHOR=Li Yi , Lu Juan , Hou Yujun , Huang Shichao , Pei Gang TITLE=Alzheimer’s Amyloid-β Accelerates Human Neuronal Cell Senescence Which Could Be Rescued by Sirtuin-1 and Aspirin JOURNAL=Frontiers in Cellular Neuroscience VOLUME=16 YEAR=2022 URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.906270 DOI=10.3389/fncel.2022.906270 ISSN=1662-5102 ABSTRACT=

Cellular senescence is a major biological process related to aging. Neuronal cell senescence contributes to the pathogenesis of many aging-related neurodegenerative diseases including Alzheimer’s disease (AD). In this study, we showed that amyloid-β42 oligomers (Aβ), one of the core pathological players of AD, significantly upregulated the expression of senescence markers, p21, plasminogen activator inhibitor-1 (PAI-1), and SA-β-gal (senescence-associated β-galactosidase) in multiple human neuronal cells, including SK-N-SH cells, SH-SY5Y cells, and neural stem cell (NSC)-derived neuronal cells. Moreover, it was consistently observed among the cells that Aβ promoted senescence-associated DNA damage as the levels of 8-OHdG staining, histone variant H2AX phosphorylation (γ-H2AX), and genomic DNA lesion increased. Mechanism study revealed that the exposure of Aβ markedly suppressed the expression of sirtuin-1 (SIRT1), a critical regulator of aging, and the exogenous expression of SIRT1 alleviated Aβ-induced cell senescence phenotypes. To our surprise, a widely used cardiovascular drug aspirin considerably rescued Aβ-induced cellular senescence at least partially through its regulation of SIRT1. In conclusion, our findings clearly demonstrate that exposure of Aβ alone is sufficient to accelerate the senescence of human neuronal cells through the downregulation of SIRT1.