Leptin inhibits amyloid β-protein fibrillogenesis by decreasing GM1 gangliosides on the neuronal cell surface through PI3K/Akt/mTOR pathway

Leptin is a centrally acting hormone that controls metabolic pathways. Recent epidemiological studies suggest that plasma leptin is protective against Alzheimer's disease. However, the mechanism that underlies this effect remains uncertain. To investigate whether leptin inhibits the assembly of amyloid -protein (A) on the cell surface of neurons, we treated primary neurons with leptin. Leptin treatment decreased the GM1 ganglioside (GM1) levels in the detergent-resistant membrane microdomains (DRMs) of neurons. The increase in GM1 expression induced by leptin was inhibited after pre-treatment with inhibitors of phosphatidylinositol 3-kinase (LY294002), Akt (triciribine) and the mammalian target of rapamycin (i.e. rapamycin), but not by an inhibitor of extracellular signal-regulated kinase (PD98059). In addition, pre-treatment with these reagents blocked the induction of GM1 in DRMs by leptin. Furthermore, A assembly on the cell surface of neurons was inhibited greatly after treatment with leptin. This reduction was markedly inhibited after pre-treatment with LY294002, triciribine, and rapamycin. These results suggest that leptin significantly inhibits A assembly by decreasing GM1 expression in DRMs of the neuronal surface through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway.