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

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。

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.