Chung Ming-Min, Nicol Christopher J, Cheng Yi-Chuan, Lin Kuan-Hung, Chen Yen-Lin, Pei Dee, Lin Chien-Hung, Shih Yi-Nuo, Yen Chia-Hui, Chen Shiang-Jiuun, Huang Rong-Nan, Chiang Ming-Chang
Department of Internal Medicine, Cardinal Tien Hospital, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan.
Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Division of Cancer Biology & Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Exp Cell Res. 2017 Mar 1;352(1):75-83. doi: 10.1016/j.yexcr.2017.01.017. Epub 2017 Feb 1.
A growing body of evidence suggests type 2 diabetes mellitus (T2DM) is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Although the precise mechanisms remain unclear, T2DM may exacerbate neurodegenerative processes. AMP-activated protein kinase (AMPK) signaling is an evolutionary preserved pathway that is important during homeostatic energy biogenesis responses at both the cellular and whole-body levels. Metformin, a ubiquitously prescribed anti-diabetic drug, exerts its effects by AMPK activation. However, while the roles of AMPK as a metabolic mediator are generally well understood, its performance in neuroprotection and neurodegeneration are not yet well defined. Given hyperglycemia is accompanied by an accelerated rate of advanced glycosylation end product (AGE) formation, which is associated with the pathogenesis of diabetic neuronal impairment and, inflammatory response, clarification of the role of AMPK signaling in these processes is needed. Therefore, we tested the hypothesis that metformin, an AMPK activator, protects against diabetic AGE induced neuronal impairment in human neural stem cells (hNSCs). In the present study, hNSCs exposed to AGE had significantly reduced cell viability, which correlated with elevated inflammatory cytokine expression, such as IL-1α, IL-1β, IL-2, IL-6, IL-12 and TNF-α. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. In addition, metformin rescued the transcript and protein expression levels of acetyl-CoA carboxylase (ACC) and inhibitory kappa B kinase (IKK) in AGE-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses, and metformin did prevent the AGE-mediated increase in NF-κB mRNA and protein levels in the hNSCs exposed to AGE. Indeed, co-treatment with metformin significantly restored inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) levels in AGE-treated hNSCs. These findings extend our understanding of the central role of AMPK in AGE induced inflammatory responses, which increase the risk of neurodegeneration in diabetic patients.
越来越多的证据表明，2型糖尿病（T2DM）与神经退行性疾病如阿尔茨海默病（AD）有关。尽管确切机制尚不清楚，但T2DM可能会加剧神经退行性过程。AMP激活的蛋白激酶（AMPK）信号通路是一条在细胞和全身水平的稳态能量生物合成反应中起重要作用的进化保守通路。二甲双胍是一种广泛使用的抗糖尿病药物，通过激活AMPK发挥作用。然而，虽然AMPK作为代谢介质的作用已得到普遍了解，但其在神经保护和神经退行性变中的作用尚未明确界定。鉴于高血糖伴随着晚期糖基化终产物（AGE）形成速率的加快，这与糖尿病性神经元损伤的发病机制以及炎症反应有关，因此需要阐明AMPK信号通路在这些过程中的作用。因此，我们测试了一个假设，即AMPK激活剂二甲双胍可保护人类神经干细胞（hNSCs）免受糖尿病AGE诱导的神经元损伤。在本研究中，暴露于AGE的hNSCs细胞活力显著降低，这与炎症细胞因子如IL-1α、IL-1β、IL-2、IL-6、IL-12和TNF-α的表达升高相关。二甲双胍联合治疗显著消除了AGE对hNSCs的影响。此外，二甲双胍挽救了AGE处理的hNSCs中乙酰辅酶A羧化酶（ACC）和抑制性κB激酶（IKK）的转录和蛋白表达水平。NF-κB是一种转录因子，在多种参与炎症反应的基因表达中起关键作用，二甲双胍确实阻止了AGE介导的暴露于AGE的hNSCs中NF-κB mRNA和蛋白水平的增加。事实上，二甲双胍联合治疗显著恢复了AGE处理的hNSCs中诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的水平。这些发现扩展了我们对AMPK在AGE诱导的炎症反应中的核心作用的理解，而这种炎症反应会增加糖尿病患者神经退行性变的风险。
