Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein
Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein
复制标题
DOI：
10.1111/j.1471-4159.2006.04368.x
复制
发表时间：
2007-05-01
影响因子：
4.7
通讯作者：
Hoyer, Siegfried
中科院分区：
文献类型：
--
作者：
Gruenblatt, Edna;Salkovic-Petrisic, Melita;Hoyer, Siegfried
用3月龄大鼠脑室注射小剂量链脲佐菌素(STZ)探讨脑胰岛素系统功能障碍。STZ icv治疗3个月后，INS-1和INS-2mRNA在海马区和额顶叶皮质的表达分别显著降低至11%和28%。胰岛素受体(IR)mRNA在额顶叶大脑皮层和海马区的表达显著降低(分别为对照组的16%和33%)。在蛋白质/活性水平，蛋白酪氨酸激酶活性(海马区增加)、总IRβ亚基(下丘脑减少)和磷酸化IR酪氨酸残基(增加)均出现不同程度的异常。侧脑室应用葡萄糖转运抑制剂并不能消除STZ诱导的学习和记忆能力障碍，这种药物可以预防STZ诱导的糖尿病。IR基因表达降低和磷酸化IR酪氨酸残基/蛋白酪氨酸激酶活性升高之间的差异可能表明IRβ亚基的磷酸化/去磷酸化之间的失衡导致其功能障碍。这些异常可能指向应用STZ icv后复杂的脑胰岛素系统功能障碍，这可能导致过度磷酸化的tau蛋白浓度增加。脑胰岛素系统功能障碍可能是导致tau蛋白过度磷酸化的病理核心，作为散发性阿尔茨海默病的形态标志。
The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR beta-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus. The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR beta-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tau-protein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.