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.

中文翻译：

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二甲双胍预处理通过 mTOR 依赖性 PP2A 和 GSK-3β 激活防止微囊藻毒素-LR 诱导的 tau 过度磷酸化

微囊藻毒素-亮氨酸-精氨酸 (MC-LR) 是淡水蓝藻分泌的一种毒素，被认为是阿尔茨海默病 (AD) 的潜在环境风险因素。先前的一项研究表明，通过蛋白磷酸酶 2A (PP2A) 和 GSK-3β 抑制引起的 tau 蛋白过度磷酸化是 MC-LR 诱导神经毒性的机制；然而，如何有效预防 MC-LR 诱导的神经毒性仍不清楚。在这项研究中，研究了二甲双胍对 MC-LR 诱导的神经毒性的逆转作用。结果表明，二甲双胍通过 PP2A 和 GSK-3b 活性有效阻止了 MC-LR 引起的 Ser202 上的 tau 过度磷酸化。二甲双胍对 PP2A 活性的影响取决于对 MC-LR 处理的 SH-SY5Y 细胞中 mTOR 的抑制。二甲双胍可防止海马内 MC-LR 给药引起的大鼠空间记忆缺陷。总之，结果表明二甲双胍可以通过阻止 Ser202 处的 tau 磷酸化来改善 MC-LR 诱导的 AD 样表型，这主要由 mTOR 依赖性 PP2A 和 GSK-3β 激活介导。