Pretreatment with metformin prevents microcystin-LR-induced tau hyperphosphorylation via mTOR-dependent PP2A and...

Area of Science:

• Neuroscience
• Toxicology
• Pharmacology

Background:

• Microcystin-leucine-arginine (MC-LR) is a cyanobacterial toxin associated with Alzheimer's disease (AD) risk.
• MC-LR induces neurotoxicity by promoting tau hyperphosphorylation via protein phosphatase 2A (PP2A) and GSK-3β.
• Effective prevention strategies for MC-LR-induced neurotoxicity are currently lacking.

Purpose of the Study:

• To investigate the potential of metformin in reversing MC-LR-induced neurotoxicity.
• To elucidate the molecular mechanisms underlying metformin's protective effects against MC-LR.

Main Methods:

• MC-LR-induced neurotoxicity was modeled in SH-SY5Y cells and in rat models.
• The effects of metformin on tau phosphorylation, PP2A, GSK-3β, and mTOR activity were assessed.
• Spatial memory deficits were evaluated in rats following MC-LR administration and metformin treatment.

Main Results:

• Metformin effectively prevented MC-LR-induced tau hyperphosphorylation at Ser202.
• Metformin's action on PP2A activity was dependent on the inhibition of mTOR in MC-LR-treated cells.
• Metformin administration ameliorated spatial memory impairments in rats exposed to MC-LR.

Conclusions:

• Metformin demonstrates a significant reversal effect on MC-LR-induced neurotoxicity.
• The protective mechanism involves preventing tau phosphorylation at Ser202 via mTOR-dependent PP2A and GSK-3β pathways.
• Metformin shows promise as a therapeutic agent for mitigating AD-like phenotypes induced by environmental toxins like MC-LR.