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Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein

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 β‐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 β‐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.