Exendin-4, a glucagon-like Peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes.
Exendin-4, a glucagon-like Peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes.
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Exendin-4 是一种胰高血糖素样 Peptide-1 受体激动剂，可减少 2 型糖尿病大鼠海马中与阿尔茨海默病相关的 tau 蛋白过度磷酸化。
DOI：
10.1097/jim.0000000000000129
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发表时间：
2015
影响因子：
2.6
通讯作者：
Hu Shuhong
中科院分区：
文献类型：
--
作者：
Xu Weijie;Yang Yan;Yuan Gang;Zhu Wenjun;Ma Delin;Hu Shuhong
研究背景2型糖尿病（T2 D）患者脑内胰岛素信号通路受损是阿尔茨海默病（Alzheimer disease，AD）的危险因素。胰高血糖素样肽-1（GLP-1）及其受体激动剂广泛用于治疗T2 D。在这里，我们研究了毒蜥外泌肽-4（EX-4），一种长效GLP-1受体激动剂，是否可以降低AD在T2D.Materials和方法的风险2型糖尿病大鼠注射EX-4连续28天。在实验期间测定血糖和胰岛素水平以及脑脊液中的GLP-1和胰岛素。tau蛋白在各个磷酸化位点的磷酸化水平，磷脂酰肌醇3激酶/蛋白激酶B的活性结果EX-4干预后，T2 D大鼠海马tau蛋白Ser 199/202和Thr 217磷酸化水平显著升高，磷酸化水平显著降低。此外，EX-4处理后脑胰岛素信号通路得到改善，这一结果反映在T2 D大鼠海马中PI 3 K/AKT活性降低和GSK-3β活性升高，以及EX-4干预4周后PI 3 K/AKT活性升高和GSK-3β活性降低。4似乎可以防止AD相关tau蛋白的过度磷酸化，这是由于脑中胰岛素信号传导途径增加所致。这些发现支持GLP-1在T2 D个体中预防和治疗AD的潜在用途。
BackgroundImpaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D.Materials and MethodsType 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3β (GSK-3β) were analyzed with Western blots.ResultsThe levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3β in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3β activity after 4 weeks intervention of EX-4.ConclusionsThese results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D.