Exendin-4通过Wnt通路减轻2型糖尿病大脑Alzheimer病样改变的机制

Type 2 diabetes mellitus (T2DM) increased the risk for developing Alzheimer's disease(AD), and brain insulin played a critical role in maintaining the pathophysiological changes of AD-associated tau protein. Recent studies have concluded that canonical Wnt signaling might be a therapeutic target for AD treatment. In our previous work, we found that brain insulin was decreased and tau protein was hyperphosphorylated. Exendin-4(Ex-4), a GLP-1 receptor agonist increased the level of brain insulin, as well as ameliorated AD-like tau changes. Moreover, EX-4 could activate Wnt signaling and the Wnt signaling was closely related with insulin production. Thus, Wnt signaling might be involved in the development of AD in T2DM by Ex-4. Based on those findings, using insulin or β-catenin central knockout mice and adenovirus-mediated transfection, we will further investigate: (1) the molecular mechanisms of Wnt signaling in the regulation of AD in T2DM by Ex-4; (2) the mechanisms of “crosstalk between nuclear factors”contributing to the production of brain insulin by activated Wnt signaling. Our study will further clarify the role of Ex-4 and Wnt signaling in the regulation of brain insulin, which might provide more evidence for decreasing the risk of AD in T2DM.

2型糖尿病（T2DM）已成为Alzheimer病（AD）的发病风险。研究显示，大脑胰岛素在维持AD相关性病理生理变化中起到重要作用，经典Wnt通路可能是治疗AD的靶点。本课题组前期研究发现：T2DM时大脑胰岛素下降合并tau蛋白AD相关病变，GLP-1受体激动剂Ex-4可增加大脑胰岛素并减轻tau蛋白AD相关病变；进而发现：Ex-4可激活Wnt通路，而后者与胰岛素生成密切相关。因此，Wnt通路的激活可能是Ex-4通过提高大脑胰岛素水平改善T2DM时AD相关性病变的关键环节。本课题将利用insulin、β-catenin中枢特异性条件敲除小鼠和腺病毒转染等方法，开展以下研究：1揭示Wnt通路参与Ex-4改善T2DM大脑胰岛素水平的现象；2阐明Wnt通路通过“核因子对话”产生胰岛素和改善AD相关性病变的分子机制。本课题的开展，将有助于全面揭示Ex-4通过Wnt通路降低T2DM时AD病变的机制。

2型糖尿病（T2DM）已成为Alzheimer病（AD）的发病风险。T2DM发生AD的风险显著高于非T2DM人群，且T2DM与AD目前均无治愈手段，因此防治及逆转T2DM时AD的早期病变已成为治疗的关键。研究显示，大脑胰岛素在维持AD相关性病理生理变化中起到重要作用，经典Wnt通路可能是治疗AD的靶点。因此本研究的主要内容为：1.揭示Wnt通路参与Ex-4改善T2DM大脑胰岛素水平的现象；2.阐明Wnt通路通过“核因子对话”产生胰岛素和改善AD相关性病变的分子机制。本课题组通过细胞及动物实验研究发现：1.Ex-4通过促进脑胰岛素分泌改善T2DM相关AD早期病变；2. Ex-4通过激活经典Wnt通路促进脑胰岛素的分泌；3. Ex-4激活经典Wnt通路后通过调控NeuroD1因子促进脑胰岛素生成。本课题的开展，进一步阐述了 Ex-4 通过经典 Wnt 信号通路改善 T2DM 时 tau 蛋白 AD 相关性病变的作用机制及部分调控网络，有助于全面揭示Ex-4通过Wnt通路降低T2DM时AD病变的机制，对于揭示 T2DM、AD 等疾病的病理生理过程乃至药物靶点的开发均具有重要的科学意义和社会经济学效益。