Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer's disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3β, forming SGK1-GSK-3β-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3β-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.

中文翻译：

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高脂饮食诱导的SGK1活化促进阿尔茨海默氏病相关的tau病理

长期以来，人们一直认为2型糖尿病（T2DM）是阿尔茨海默氏病（AD）的危险因素。但是，T2DM和AD之间的分子联系仍然不清楚。在这里，我们报道了通过长期高脂饮食（HFD）激活了血清/糖皮质激素调节激酶1（SGK1），这增加了T2DM的风险，并因此通过Ser214处tau的磷酸化和激活促进了Tau病理。关键tau激酶，即GSK-3β，形成SGK1-GSK-3β-tau复合物。SGK1在与HFD相关的糖皮质激素升高和高血糖的条件下被激活，但不被脂肪酸介导的胰岛素抵抗激活。小鼠海马中SGK1的表达升高导致神经变性和学习记忆障碍。SGK1的上调和激活，在AD患者的海马体中也观察到SGK1-GSK-3β-tau复合物。我们的结果表明，SGK1是AD中tau病理学的关键修饰因子，将AD与皮质类固醇作用和T2DM联系起来。