Pretreatment with metformin prevents microcystin-LR-induced tau hyperphosphorylation via mTOR-dependent PP2A and GSK-3β activation.
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.
['Zhang|Yali|Y|https://orcid.org/0000-0002-0914-0021', 'Fan|Xing|X|', 'Su|Zhangyao|Z|', 'Yuan|Tianli|T|', 'Yin|Haimeng|H|', 'Gu|Haohao|H|', 'Zuo|Yue|Y|', 'Chen|Shiyin|S|', 'Zhou|Hongyu|H|', 'Su|Gaoxing|G|https://orcid.org/0000-0001-9607-2006']
D000818:Animals D000071679:Glycogen Synthase Kinase 3 beta D008387:Marine Toxins D008687:Metformin D052998:Microcystins D010766:Phosphorylation D054648:Protein Phosphatase 2 D051381:Rats D058570:TOR Serine-Threonine Kinases D016875:tau Proteins
metformin PP2A GSK-3β tau phosphorylation microcystin-LR