The protective effects of Agomelatine against Aβ1-42 oligomers-induced cellular senescence mediated by SIRT6 and Agomelatine's potential in AD treatment.

Alzheimer's disease (AD) is a vicious degenerative disease commonly observed in the elderly population, and the deposition of Amyloid β (Aβ) is regarded as the principal pathological inducement of AD. Severe oxidative stress, inflammatory reactions, and cell senescence in neurons can be induced by Aβ1-42 oligomers, which further contribute to the damage on neurons. Agomelatine is an antidepressant that is recently claimed to have promising anti-oxidative stress and anti-inflammatory effects. The present study aims to explore the potential therapeutic function of Agomelatine on AD and the possible mechanism. Aβ1-42 oligomers were used to induce an in vitro injury model in SH-SY5Y neuronal cells. First, we found that exposure to Aβ1-42 oligomers significantly exacerbated oxidative stress by increasing hydrogen peroxide production and reducing glutathione peroxidase (GPx), which were partially rescued by Agomelatine. Also, Agomelatine attenuated Aβ1-42 oligomers-induced inflammatory response by decreasing the expression of TNF-α and IL-1β. Notably, Agomelatine improved cellular senescence by reducing senescence-associated β-galactosidase (SA-β-Gal) staining and mitigating Aβ1-42 oligomers-induced reduction of telomerase activity. In addition, the upregulated p16INK4A and p21CIP1 and the suppressed expression of SIRT6 in Aβ1-42 oligomers-treated cells were reversed by Agomelatine. Lastly, after the knockdown of SIRT6, the protective effect of Agomelatine against Aβ1-42 oligomers-induced cellular senescence was significantly eliminated. In conclusion, our data indicated that Agomelatine ameliorated Aβ1-42 oligomers-induced cellular senescence mediated by SIRT6, and thus, Agomelatine could be effective in treating AD.