engleski

Brain insulin and insulin receptor dysfunction triggers Alzheimer-like pathology in an experimental rat model.

Background/aims. Decreased brain glucose/energy metabolism and cognitive deficits similar to those found in sporadic Alzheimer’ s disease (sAD) were reported in streptozotocin (STZ)-intracerebroventricularly (icv) treated rats, suggesting them as an experimental sAD model. Brain insulin receptor (IR) signaling cascade dysfunction found post mortem in sAD, has been reported recently also in STZ-icv rat model, in which brain insulin and IR activity, and tau protein as both a terminal substrate in IR signaling cascade, and a pathological marker of sAD, were here investigated. Methods. Gene expression of insulin and IR, and alterations of IR-beta subunit, protein tyrosine kinase (TK) activity and tau protein were measured by means of quantitative RT-PCR, ELISA, PTK assay and Western blot, respectively, in rat frontoparietal cortex (CTX) and hippocampus (HPC), three months following the STZ-icv (1 mg/kg) treatment. Results. The expression of insulin-1 and -2 mRNA was found significantly decreased in HPC and CTX, respectively. Both regions demonstrated significantly decreased IR mRNA expression. Significantly increased concentration of phosphorylated IR-beta subunit has been found in CTX, with no change in HPC, while significantly increased TK activity was found in HPC only. Total and phosphorylated (GSK-3 related) tau protein was significantly increased in HPC of STZ-icv rats. Conclusion. STZicv-induced discrepancy between reduced IR gene expression and increased phosphorylated IR tyrosine residues/TK activity may indicate imbalance between its phosphorylation/dephosphorylation causing IR dysfunction, and subsequently triggering tau hyperphosphorylation, which points to the brain insulin/IR dysfunction as a possible pathological core in the generation of sAD. Supported by Croatian MZOS and DAAD.

Alzheimer's Disease; Experimental Model; Streptozotocin; Brain Insulin

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