Department of Endocrinology, Tongji Hospital, Tongji Medical College of the Huazhong University of Science and Technology, Wuhan, PR China.
J Alzheimers Dis. 2013;33(2):329-38. doi: 10.3233/JAD-2012-121294.
Recent studies have demonstrated that insulin plays important roles in the brain, including regulation of glucose metabolism and modulation of learning and memory. We have found dysregulation of brain insulin signaling in both Alzheimer's disease (AD) and type 2 diabetes (T2D), which correlates to hyperphosphorylation of tau, a key abnormal tau modification leading to neurofibrillary tangles. Here, we investigated tau phosphorylation and the two key components of the insulin signaling pathway, protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β), in a rat model of T2D produced by a high protein, high glucose, and high fat diet followed by intraperitoneal injection of streptozocin. We found tau hyperphosphorylation, decreased AKT activation, and GSK-3β over-activation in T2D rat brains. Intranasal insulin treatment for four weeks normalized AKT and GSK-3β, as well as reduced tau hyperphosphorylation in T2D rat brains, whereas four-week treatments with subcutaneous insulin had minimal effects on brain GSK-3β and tau phosphorylation. These results suggest decreased brain insulin signaling and tau hyperphosphorylation in the rat model of T2D and demonstrate the efficacy of intranasal insulin treatment to reverse these brain abnormalities. Our findings provide further mechanism by which T2D increases the risk for AD and also support the potential use of intranasal insulin for the treatment of AD.
最近的研究表明，胰岛素在大脑中发挥着重要作用，包括调节葡萄糖代谢和调节学习和记忆。我们已经发现，在阿尔茨海默病（AD）和 2 型糖尿病（T2D）中，大脑胰岛素信号传导失调，这与 tau 的过度磷酸化有关，tau 是导致神经原纤维缠结的关键异常 tau 修饰。在这里，我们通过高蛋白、高葡萄糖和高脂肪饮食后腹腔注射链脲佐菌素，在 T2D 大鼠模型中研究了 tau 磷酸化和胰岛素信号通路的两个关键组成部分，蛋白激酶 B（AKT）和糖原合酶激酶-3β（GSK-3β）。我们发现 T2D 大鼠大脑中的 tau 过度磷酸化、AKT 激活减少和 GSK-3β 过度激活。鼻内胰岛素治疗 4 周可使 AKT 和 GSK-3β 正常化，并减少 T2D 大鼠大脑中的 tau 过度磷酸化，而皮下胰岛素治疗 4 周对大脑 GSK-3β 和 tau 磷酸化的影响最小。这些结果表明，T2D 大鼠模型中大脑胰岛素信号传导减少和 tau 过度磷酸化，并证明了鼻内胰岛素治疗逆转这些大脑异常的功效。我们的发现进一步提供了 T2D 增加 AD 风险的机制，并支持鼻内胰岛素用于 AD 治疗的潜在用途。
