Grünblatt Edna, Salkovic-Petrisic Melita, Osmanovic Jelena, Riederer Peter, Hoyer Siegfried
Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Laboratory, Clinic for Psychiatry and Psychotherapy, Bayrische Julius-Maximilian University of Würzburg, Würzburg, Germany.
J Neurochem. 2007 May;101(3):757-70. doi: 10.1111/j.1471-4159.2006.04368.x.
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.
采用低剂量链脲佐菌素（STZ）脑室内（icv）注射法处理3月龄大鼠，以探究脑胰岛素系统功能障碍。STZ脑室内注射处理3个月后，胰岛素-1和-2 mRNA的表达在海马体中显著降低至11%，在额顶叶大脑皮层中降低至28%。胰岛素受体（IR）mRNA表达在额顶叶大脑皮层和海马体中显著下降（分别为对照组的16%和33%）。在蛋白质/活性水平上，蛋白质酪氨酸激酶活性（海马体中增加）、总IRβ亚基（下丘脑减少）和磷酸化IR酪氨酸残基（增加）出现了不同的异常情况。已知可预防STZ诱导的糖尿病的葡萄糖转运抑制剂脑室内注射并不能消除STZ诱导的学习和记忆能力障碍。IR基因表达降低与磷酸化IR酪氨酸残基/蛋白质酪氨酸激酶活性增加之间的差异可能表明IRβ亚基磷酸化/去磷酸化失衡导致其功能障碍。这些异常情况可能表明STZ脑室内注射后存在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被认为是散发性阿尔茨海默病形态学标志物——过度磷酸化tau蛋白产生的可能病理核心。
