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

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Abstract

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.

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Acknowledgements

This study was supported by the Science and Technology Ministry of Sichuan Province (2019ZYZF0063, 2020yj0497, and 2019yyjskf06).

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Authors and Affiliations

  1. Department of Neurology, Ya’an Peoples Hospital, Ya’an, 625000, Sichuan, China

    Jian Wang & Bo Zheng

  2. Department of Neurology, The Affiliated Hospital of University of Electronic Science and Technology, Sichuan Provincial People’s Hospital, No. 32, West Second Section, First Ring Road, Qingyang District, Chengdu, 610000, Sichuan, China

    Shu Yang & Jianhong Wang

  3. West China Hospital, Innovation Center of Nursing Research, Sichuan University, Chengdu, 610041, China

    Fang Wang

  4. Nursing Key Laboratory of Sichuan Province, Sichuan University, Chengdu, 610041, China

    Fang Wang

  5. Department of Neurology, The Fifth Hospital of Deyang, 531 Huashan North Road, Jingyang District, Deyang City, 610000, Sichuan, China

    Zhonglin Wang

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  1. Jian Wang
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Correspondence to Zhonglin Wang or Jianhong Wang.

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Wang, J., Zheng, B., Yang, S. et al. The protective effects of Agomelatine against Aβ1-42 oligomers-induced cellular senescence mediated by SIRT6 and Agomelatine’s potential in AD treatment. Human Cell 34, 1734–1743 (2021). https://doi.org/10.1007/s13577-021-00611-2

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  • DOI: https://doi.org/10.1007/s13577-021-00611-2

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