Abstract
Autophagy, a lysosomal degradative pathway, is crucial for the pathogenesis of Alzheimer’s disease (AD). Schizandrol A (SchA) shows multiple pharmacological effects. However, the potential effects and mechanisms of SchA on amyloid-β (Aβ)-induced autophagy remain unclear. In this study, differentiated SH-SY5Y cells or primary hippocampal neurons were pretreated with SchA (2 μg/ml) for 1 h before subjected to Aβ1–42 (10 μM) for 24 h to test its effects on cell viability, apoptosis, oxidative stress, and autophagy. Then an mTOR inhibitor (rapamycin) and a PI3K inhibitor (LY294002) were employed to explore the role of PI3K/AKT/mTOR pathway. The results showed that SchA significantly inhibited Aβ1–42-triggered reduction of viable cells, increases of apoptotic cell number and pro-apoptotic protein expressions, as well as alterations of oxidative stress markers. In addition, the increases of LC3-II/LC3-I and Beclin-1 and decrease of p62 were suppressed by SchA. At the molecular level, we found that the inactivation of PI3K/AKT/mTOR pathway was ameliorated by SchA. Inhibition of PI3K/AKT/mTOR pathway deteriorated the protective effects of SchA against Aβ1–42-induced autophagy activation, cell death, and apoptosis. In conclusion, we demonstrate that SchA attenuates Aβ1–42-induced autophagy through activating PI3K/AKT/mTOR signaling pathway. SchA may be a novel drug for the prevention and treatment of AD.
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This study was supported by grants from the National Natural Science Foundation of China (No. 81271208) and the Scientific Research Project of Heilongjiang Provincial Health and Family Planning Commission (No. 2017-501).
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SL, YLF, and PZY conceived and designed the research. SL, YLF, and ZLM conducted the experiments. YLF and PZY contributed new reagents or analytical tools. ZLM and LYC analyzed data. SL wrote the manuscript. All authors read and approved the manuscript.
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Song, L., Yao, L., Zhang, L. et al. Schizandrol A protects against Aβ1–42-induced autophagy via activation of PI3K/AKT/mTOR pathway in SH-SY5Y cells and primary hippocampal neurons. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1739–1752 (2020). https://doi.org/10.1007/s00210-019-01792-2
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DOI: https://doi.org/10.1007/s00210-019-01792-2