Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Research Center of Pharmaceutical Nanotechnology, Chiang Mai University, Chiang Mai 50200, Thailand.
Int J Mol Sci. 2020 Mar 3;21(5):1725. doi: 10.3390/ijms21051725.
Neuronal insulin resistance is a significant feature of Alzheimer's disease (AD). Accumulated evidence has revealed the possible neuroprotective mechanisms of antidiabetic drugs in AD. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog and an antidiabetic agent, has a benefit in improving a peripheral insulin resistance. However, the neuronal effect of liraglutide on the model of neuronal insulin resistance with Alzheimer's formation has not been thoroughly investigated. The present study discovered that liraglutide alleviated neuronal insulin resistance and reduced beta-amyloid formation and tau hyperphosphorylation in a human neuroblostoma cell line, SH-SY5Y. Liraglutide could effectively reverse deleterious effects of insulin overstimulation. In particular, the drug reversed the phosphorylation status of insulin receptors and its major downstream signaling molecules including insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK-3β). Moreover, liraglutide reduced the activity of beta secretase 1 (BACE-1) enzyme, which then decreased the formation of beta-amyloid in insulin-resistant cells. This indicated that liraglutide can reverse the defect of phosphorylation status of insulin signal transduction but also inhibit the formation of pathogenic Alzheimer's proteins like Aβ in neuronal cells. We herein provided the possibility that the liraglutide-based therapy may be able to reduce such deleterious effects caused by insulin resistance. In view of the beneficial effects of liraglutide administration, these findings suggest that the use of liraglutide may be a promising therapy for AD with insulin-resistant condition.
神经元胰岛素抵抗是阿尔茨海默病（AD）的一个重要特征。越来越多的证据表明，抗糖尿病药物在 AD 中可能具有神经保护机制。利拉鲁肽是一种胰高血糖素样肽-1（GLP-1）类似物和抗糖尿病药物，它有益于改善外周胰岛素抵抗。然而，利拉鲁肽对伴有阿尔茨海默病形成的神经元胰岛素抵抗模型的神经元作用尚未得到彻底研究。本研究发现，利拉鲁肽可减轻神经元胰岛素抵抗，并减少人神经母细胞瘤细胞系 SH-SY5Y 中的β-淀粉样蛋白形成和 tau 过度磷酸化。利拉鲁肽可有效逆转胰岛素过度刺激的有害作用。特别是，该药物逆转了胰岛素受体及其主要下游信号分子（包括胰岛素受体底物 1（IRS-1）、蛋白激酶 B（AKT）和糖原合酶激酶 3β（GSK-3β）的磷酸化状态。此外，利拉鲁肽降低了β-分泌酶 1（BACE-1）酶的活性，从而减少了胰岛素抵抗细胞中β-淀粉样蛋白的形成。这表明利拉鲁肽不仅可以逆转胰岛素信号转导的磷酸化状态缺陷，还可以抑制神经元细胞中致病性阿尔茨海默病蛋白如 Aβ的形成。我们在此提供了基于利拉鲁肽的治疗可能能够减轻由胰岛素抵抗引起的这种有害影响的可能性。鉴于利拉鲁肽给药的有益效果，这些发现表明，使用利拉鲁肽可能是治疗伴有胰岛素抵抗的 AD 的一种有前途的方法。
