Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain Implication for Alzheimer's Disease
Dysregulation of Insulin Signaling, Glucose Transporters, O-GlcNAcylation, and Phosphorylation of Tau and Neurofilaments in the Brain Implication for Alzheimer's Disease
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DOI：
10.2353/ajpath.2009.090157
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发表时间：
2009-11-01
影响因子：
6
通讯作者：
Gong, Cheng-Xin
中科院分区：
文献类型：
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作者：
Deng, Yanqiu;Li, Bin;Gong, Cheng-Xin
最近的研究表明，胰岛素功能障碍可能在散发性阿尔茨海默病（AD）的发病机制中发挥作用。在AD中，脑葡萄糖代谢受损，并且这种受损似乎先于疾病的病理和临床症状。然而，受损的胰岛素信号传导对AD的确切贡献尚不清楚。在这项研究中，通过使用非转基因大鼠模型的散发性AD产生的侧脑室注射链脲佐菌素，我们研究了胰岛素信号，葡萄糖转运蛋白，蛋白O-GlcNAc酰化，和磷酸化的tau蛋白和神经丝在大脑中。我们发现胰岛素信号传导受损，糖原合成酶激酶-3 β过度活化，主要脑葡萄糖转运蛋白水平降低，蛋白质O-GlcNAc化下调，tau和神经丝磷酸化增加，以及链脲佐菌素治疗大鼠脑中tau微管结合活性降低。这些结果表明，受损的脑胰岛素信号传导可能导致糖原合成酶激酶-3 β的过度活化和O-GicNAc化的下调，这反过来又促进tau蛋白和神经丝的异常过度磷酸化，从而导致神经退行性变。(Am j Pathol 2009，175：2089-2098; DOI：10.2353/ajpath.2009.090157）
Recent studies have suggested a possible role of insulin dysfunction in the pathogenesis of sporadic Alzheimer's disease (AD). in AD, brain glucose metabolism is impaired, and this impairment appears to precede the pathology and clinical symptoms of the disease. However, the exact contribution of impaired insulin signaling to AD is not known. In this study, by using a nontransgenic rat model of sporadic AD generated by intracerebroventricular administration of streptozotocin, we investigated insulin signaling, glucose transporters, protein O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain. We found impaired insulin signaling, overactivation of glycogen synthase kinase-3 beta, decreased levels of major brain glucose transporters, down-regulated protein O-GlcNAcylation, increased phosphorylation of tau and neurofilaments, and decreased microtubule-binding activity of tau in the brains of streptozotocin-treated rats. These results suggest that impaired brain insulin signaling may lead to overactivation of glycogen synthase kinase-3 beta and down-regulation of O-GicNAcylation, which, in turn, facilitate abnormal hyperphosphorylation of tau and neurofilaments and, consequently, neurofibrillary degeneration. (Am j Pathol 2009,175:2089-2098; DOI: 10.2353/ajpath.2009.090157)