Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein |
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Authors: | Grünblatt Edna Salkovic-Petrisic Melita Osmanovic Jelena Riederer Peter Hoyer Siegfried |
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Institution: | Clinical Neurochemistry and National Parkinson Foundation Centre of Excellence Laboratory, Clinic for Psychiatry and Psychotherapy, Bayrische Julius-Maximilian University of Würzburg, Würzburg, Germany. edna.gruenblatt@mail.uni-wuerzburg.de |
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Abstract: | 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. |
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Keywords: | Alzheimer's disease brain gene expression glucose transporter 2 insulin insulin receptor learning/memory protein tyrosine kinase streptozotocin tau protein |
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