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
  • 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.
PMID: 34432352 DOI: 10.1002/tox.23354
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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