Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain
Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain
复制标题
DOI：
10.1016/j.brainres.2011.01.084
复制
发表时间：
2011-04
期刊：
影响因子：
2.9
通讯作者：
Zhongsen Qu;Z. Jiao;Xiao-jiang Sun;Yu-wu Zhao;Jin-peng Ren;Guogang Xu
中科院分区：
文献类型：
--
作者：
Zhongsen Qu;Z. Jiao;Xiao-jiang Sun;Yu-wu Zhao;Jin-peng Ren;Guogang Xu
脑蛋白激酶B(Akt)和糖原合成酶-3(GSK-3)的活性对体内外周血糖水平的变化具有适应性。GSK-3在多个位点磷酸化微管相关蛋白tau，该作用可被蛋白磷酸酶-2A(PP-2A)拮抗。这些酶之间的失衡可能与糖尿病(DM)和阿尔茨海默病(AD)有关。本研究采用链脲佐菌素(STZ)建立糖尿病大鼠高血糖模型。用特异性抗体检测大鼠海马区tau蛋白的磷酸化。胰岛素和Li2CO3给药也被用来找出这些激酶的调节作用。我们观察到，在STZ诱导的DM模型中，大鼠海马tau在Ser396/Ser404(PHF-1位点)处过度磷酸化，并伴有Akt、GSK-3和PP-2A的磷酸化水平降低。GSK-3的特异性抑制剂锂在30天内几乎逆转了上述位点tau的全部磷酸化。胰岛素治疗可恢复糖尿病大鼠的血糖水平，但抑制PP-2A活性，导致tau的PHF-1位点不被去磷酸化。这些结果表明，STZ诱导的高血糖可能导致大鼠脑内Akt/GSK-3/PP-2A调节紊乱，进而导致海马tau的异常磷酸化。
Brain protein kinase B (Akt) and glycogen synthase kinase-3 (GSK-3) activities are adaptable to changes of peripheral blood glucose level in vivo. GSK-3 phosphorylates microtube-associated protein tau at multiple sites, which can be antagonized by protein phosphatase-2A (PP-2A). The imbalance among these enzymes might have potential connections with diabetes mellitus (DM) and Alzheimer's disease (AD). In this study hyperglycemia rat DM model was achieved by streptozotocin (STZ) treatment. The phosphorylation of tau in the rat hippocampus was detected with specific antibodies. Insulin and Li2CO3administration were also employed to find out the regulatory efforts of the kinases. We observed that rat hippocampus tau was hyperphosphorylated at Ser396/Ser404(PHF-1 sites) in STZ-induced DM model, accompanied by lowered phosphorylation levels of Akt, GSK-3 and PP-2A. Lithium, a specific GSK-3 inhibitor, nearly reversed all phosphorylation of tau at above sites in 30days. Insulin administration restored the blood glucose level in DM rats but suppressed PP-2A activity, resulting in the PHF-1 sites of tau not being dephosphorylated. These findings strongly suggest that STZ-induced hyperglycemia may cause disorder of Akt/GSK-3/PP-2A regulations in rat brain and further lead to abnormal phosphorylation of hippocampus tau.