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  • Schizandrol A protects against Aβ1-42-induced autophagy via activation of PI3K/AKT/mTOR pathway in SH-SY5Y cells and primary hippocampal neurons.

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 archives of pharmacology (2020-01-05)
Lin Song, Lifen Yao, Limei Zhang, Zhongyuan Piao, Yichan Lu
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
JC-1, solid
Supelco
Rapamycin, VETRANAL®, analytical standard
Sigma-Aldrich
Thiazolyl Blue Tetrazolium Bromide, 98%