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

Authors

  • Naoki Yamamoto,

    Corresponding author
    1. Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan
    2. Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
    • Address correspondence and reprint requests to Naoki Yamamoto, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, 920-1181, Japan. E-mail: na-yamam@hokuriku-u.ac.jp

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  • Mamoru Tanida,

    1. Laboratory of Applied Physiology, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
    2. Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa, Japan
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  • Rika Kasahara,

    1. Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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  • Kazuya Sobue,

    1. Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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  • Kenji Suzuki

    1. Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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Abstract

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.

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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.

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