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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain Diseases / chemically induced
  • Brain Diseases / metabolism*
  • Brain Diseases / physiopathology
  • Enzyme-Linked Immunosorbent Assay / methods
  • Injections, Intraventricular / methods
  • Insulin / metabolism*
  • Male
  • Maze Learning / drug effects
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Statistics, Nonparametric
  • Streptozocin
  • Time Factors
  • tau Proteins / metabolism*


  • Insulin
  • RNA, Messenger
  • tau Proteins
  • Streptozocin
  • Protein-Tyrosine Kinases
  • Receptor, Insulin