Both Activation and Inhibition of SIRT1 May Act via Exosomal GSK3/in the in-vitro Amyloid-beta Toxicity Model
Journal Title: Advances in Clinical Toxicology - Year 2019, Vol 4, Issue 4
Abstract
The neurodegenerative diseases such as Alzheimer’s disease (AD) become more common globally due to great effort on providing longer lifespans for human beings. Besides, the researches related to amelioration of age- related diseases by epigenetic influences gain acceleration to solve the molecular mechanism of these diseases or to improve care and opportunities of the patients. Herein, we aimed to investigate the neuroprotective and/or therapeutic effects of both SIRT1 activation and inhibition as an epigenetic influence on the exosome releasing amount and exosomal protein content in the human neuroblastoma cell line under Aβ toxicity. Cells were treated with SIRT1 activator (CAY10602, 20 µM) and SIRT1 inhibitor (Ex527, 80µM) after or before Aβ toxicity. Addition to LDH cytotoxicity tests, cell lysates and immunoprecipitated exosome samples were analyzed by western blot with respect to proteins in the PI3K/AKT/GSK3/mTOR pathway. According to the western blot analysis, SIRT1 inhibitor increased the level of phosphorylated AKT, and inhibits the GSK3α and GSK3β by increasing their phosphorylated levels; also, it decreased the amount of phosphorylated mTOR. Therefore, SIRT1 inhibitor might have protective and therapeutic effect on amyloid beta toxicity. On the other hand, SIRT1 activator increased the level of SIRT1 protein and PTEN phosphorylation. In the exosomal content, Aβ toxicity increased the level of GSK3β and decreased its phosphorylation. Interestingly, both SIRT1 activator and inhibitor produced similar neuroprotective and therapeutic effect on the Aβ toxicity in the exosomes. These results indicate that SIRT1 inhibitor and activator may be neuroprotective in the pathophysiology of AD in particular points through different molecular pathways.
Authors and Affiliations
Kalkan R, Sarikamiş B, Elibol B, Gunay N and Kilic U*
Keywords
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- EP ID EP751681
- DOI 10.23880/act-16000175
- Views 1
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