Leptin inhibits amyloid β-protein fibrillogenesis by decreasing GM1 gangliosides on the neuronal cell surface through PI3K/Akt/mTOR pathway
Article first published online: 8 AUG 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 131, Issue 3, pages 323–332, November 2014
How to Cite
J. Neurochem. (2014) 131, 323–332.
- Issue published online: 20 OCT 2014
- Article first published online: 8 AUG 2014
- Accepted manuscript online: 21 JUL 2014 02:25AM EST
- Manuscript Accepted: 17 JUL 2014
- Manuscript Revised: 14 JUL 2014
- Manuscript Received: 21 FEB 2014
- Takeda Science Foundation. Grant Number: 25870906
- Ritsumeikan Global Innovation Research Organization
- Ritsumeikan University
- Hokuriku University
- Alzheimer's disease;
- amyloid beta protein;
- GM1 ganglioside;
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 β-protein (Aβ) 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, Aβ 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 Aβ assembly by decreasing GM1 expression in DRMs of the neuronal surface through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway.
These findings highlight the importance of understanding the function of leptin in AD brains. In this study, our aim was to determine whether leptin regulates the expression and localization of GM1 on the neuronal membrane and if it induces the formation of Aβ assembly on the cell surface of neurons. Our results suggest that leptin regulates the expression of GM1 in DRMs of the neuronal membranes. Moreover, leptin does not seem to facilitate fibrillogenesis of exogenously added soluble Aβ from the cell surface of neurons.