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  2. Pretreatment with metformin prevents microcystin-LR-induced tau hyperphosphorylation via mTOR-dependent PP2A and GSK-3β activation

Pretreatment with metformin prevents microcystin-LR-induced tau hyperphosphorylation via mTOR-dependent PP2A and GSK-3β activation

  • Environ Toxicol. 2021 Dec;36(12):2414-2425. doi: 10.1002/tox.23354.
Yali Zhang 1 Xing Fan 1 Zhangyao Su 1 Tianli Yuan 1 Haimeng Yin 1 Haohao Gu 1 Yue Zuo 1 Shiyin Chen 1 Hongyu Zhou 2 Gaoxing Su 3
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, China.
  • 2 Institute of Environmental Research at Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou, China.
  • 3 School of Pharmacy, Nantong University, Nantong, China.
Abstract

Microcystin-leucine-arginine (MC-LR) is a toxin secreted by freshwater cyanobacteria that is considered a potential environmental risk factor for Alzheimer's disease (AD). A previous study indicated that Tau Protein hyperphosphorylation via protein Phosphatase 2A (PP2A) and GSK-3β inhibition was the mechanism by which MC-LR induces neurotoxicity; however, how MC-LR-induced neurotoxicity can be effectively prevented remains unclear. In this study, the reversal effect of metformin on MC-LR-induced neurotoxicity was investigated. The results showed that metformin effectively prevented tau hyperphosphorylation at Ser202 caused by MC-LR through PP2A and GSK-3b activity. The effect of metformin on PP2A activity was dependent on the inhibition of mTOR in MC-LR-treated SH-SY5Y cells. Metformin prevented spatial memory deficits in rats caused by intrahippocampal MC-LR administration. In sum, the results suggested that metformin can ameliorate the MC-LR-induced AD-like phenotype by preventing tau phosphorylation at Ser202, which was mainly mediated by mTOR-dependent PP2A and GSK-3β activation.

Keywords

GSK-3β; PP2A; metformin; microcystin-LR; tau phosphorylation.

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