Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/β-catenin/NeuroD1 pathway.
Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/β-catenin/NeuroD1 pathway.
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DOI：
10.1186/s10020-023-00718-2
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发表时间：
2023-09-04
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2型糖尿病（T2 D）是阿尔茨海默病（AD）的独立危险因素。Exendin-4（Ex-4）是一种广泛应用于治疗2型糖尿病的胰高血糖素样肽-1受体激动剂药物，对糖尿病性脑病（diabetic encephalopathy，DE）具有良好的治疗作用。特别是，Ex-4改善DE中的tau过度磷酸化和认知障碍。这些重要的改变也是T2 D和AD之间的重要桥梁。然而，其独特的机制尚不清楚。 招募db/db小鼠、高脂饮食（HFD）/链脲佐菌素（STZ）诱导的糖尿病（HF-糖尿病）小鼠和高糖损伤（HGD）HT-22海马细胞以检查Ex-4对T2 D中AD样变化的影响。采用新物体再认测验（NORT）和Morris水迷宫测验（MWMT）评价认知功能障碍。采用Dickkopf-1（DKK 1）抑制Wnt/β-catenin通路的激活，探讨Ex-4保护脑功能的机制。JASPAR是基于预测NeuroD 1和Ins 2的启动子区域之间的相互作用。此外，染色质免疫沉淀结合定量聚合酶链反应（ChIP-qPCR）和荧光素酶报告基因测定进行。 Ex-4减轻了db/db小鼠、HF糖尿病小鼠和HGD HT-22海马神经元细胞中的tau过度磷酸化，增加了脑源性胰岛素，并改善了PI 3 K/AKT/GSK 3-β信号传导。NORT和MWMT结果表明，Ex-4能改善HF糖尿病小鼠的学习记忆障碍。Wnt/β-连环蛋白通路的抑制剂Dickkopf-1（DKK 1）显著阻断了Ex-4的保护作用。关于进一步的分子机制，NeuroD 1在体内和体外受到Ex-4的影响，NeuroD 1的敲低或过表达表明其在Ex-4促进脑胰岛素中的关键作用。同时，ChIP PCR和荧光素酶报告基因检测证实了NeuroD 1和胰岛素编码基因Ins 2的启动子区域之间的结合。Ex-4能促进这种相互作用。我们的研究表明，Ex-4通过增加T2 D中的Wnt/β-catenin/NeuroD 1信号传导的Ins 2衍生的脑胰岛素来减轻tau过度磷酸化和认知功能障碍。同时也为2型糖尿病的DE治疗靶点的研究进展和机制提供了新的思路。在线版本包含补充材料，可通过10.1186/s10020-023-00718-2获得。
Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear. The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)—induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/β-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed. Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-β signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/β-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4. Our study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/β-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D. The online version contains supplementary material available at 10.1186/s10020-023-00718-2.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
4.7
作者：
Liu Y;Liu F;Grundke-Iqbal I;Iqbal K;Gong CX
通讯作者：
Gong CX
影响因子：
3.6
作者：
Lee J;Kim K;Yu SW;Kim EK
通讯作者：
Kim EK
影响因子：
3.5
作者：
Boutajangout A;Wisniewski T
通讯作者：
Wisniewski T
影响因子：
3.7
作者：
Jose Ramos-Rodriguez, Juan;Ortiz, Oscar;Garcia-Alloza, Monica
通讯作者：
Garcia-Alloza, Monica