Rat brain glucose transporter-2, insulin receptor and glial expression are acute targets of intracerebroventricular streptozotocin: risk factors for sporadic Alzheimer’s disease?
Accumulated evidence suggests that the insulin-resistant brain state and cerebral glucose hypometabolism might be the cause, rather than the consequence, of the neurodegeneration found in a sporadic Alzheimer’s disease (sAD). We have explored whether the insulin receptor (IR) and the glucose transporter-2 (GLUT2), used here as their markers, are the early targets of intracerebroventricularly (icv) administered streptozotocin (STZ) in an STZ-icv rat model of sAD, and whether their changes are associated with the STZ-induced neuroinflammation. The expression of IR, GLUT2 and glial fibrillary acidic protein (GFAP) was measured by immunofluorescence and western blot analysis in the parietal (PC) and the temporal (TC) cortex, in the hippocampus (HPC) and the hypothalamus. One hour after the STZ-icv administration (1.5 mg/kg), the GFAP immunoreactivity was significantly increased in all four regions, thus indicating the wide spread neuroinflammation, pronounced in the PC and the HPC. Changes in the GLUT2 (increment) and the IR (decrement) expression were mild in the areas close to the site of the STZ injection/release but pronounced in the ependymal lining cells of the third ventricle, thus indicating the possible metabolic implications. These results, together with the finding of the GLUT2-IR co-expression, and also the neuronal IR expression in PC, TC and HPC, indicate that the cerebral GLUT2 and IR should be further explored as the possible sAD etiopathogenic factors. It should be further clarified whether their alterations are the effect of a direct STZ-icv toxicity or they are triggered in a response to STZ-icv induced neuroinflammation.
KeywordsStreptozotocin Alzheimer’s disease Glucose transporter 2 Insulin receptor
Supported by University of Zagreb (funds awarded to M. Salkovic-Petrisic, 2015–2016), AMAC-UK (funds awarded to U. Smailovic, 2013) and the Edda Neele Stiftung (funds awarded to M. Salkovic-Petrisic). Z. Mikloska, Ph.D. is thanked for English editing.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
- Deng Y, Li B, Liu Y et al (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer’s disease. Am J Pathol 175:2089–2098. doi: 10.2353/ajpath.2009.090157 CrossRefPubMedPubMedCentralGoogle Scholar
- Dias C, Barbosa RM, Laranjinha J, Ledo A (2014) Evaluation of mitochondrial function in the CNS of rodent models of Alzheimer’s disease—high resolution respirometry applied to acute hippocampal slices. Free Radic Biol Med 75(Suppl 1):S37. doi: 10.1016/j.freeradbiomed.2014.10.780 CrossRefPubMedGoogle Scholar
- Giorgino F, Chen JH, Smith RJ (1992) Changes in tyrosine phosphorylation of insulin receptors and a 170,000 molecular weight nonreceptor protein in vivo in skeletal muscle of streptozotocin-induced diabetic rats: effects of insulin and glucose. Endocrinology 130:1433–1444. doi: 10.1210/endo.130.3.1531627 PubMedGoogle Scholar
- Goud BJ, Dwarakanath V, Swamy BKC (2015) Streptozotocin—a diabetogenic agent in animal models. Int J Pharm Pharm Res 3:253–269Google Scholar
- Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press, AmsterdamGoogle Scholar
- Salkovic-Petrisic M, Tribl F, Schmidt M et al (2006) Alzheimer-like changes in protein kinase B and glycogen synthase kinase-3 in rat frontal cortex and hippocampus after damage to the insulin signalling pathway. J Neurochem 96:1005–1015. doi: 10.1111/j.1471-4159.2005.03637.x CrossRefPubMedGoogle Scholar
- Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P (2013) What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J Neural Transm 120:233–252. doi: 10.1007/s00702-012-0877-9 CrossRefPubMedGoogle Scholar