Down regulation of brain cellular prion protein in an animal model of insulin resistance: Possible implication in increased prevalence of stroke in pre-diabetics/diabetics

The risk of stroke is drastically increased in diabetic and pre-diabetic patients. The worldwide spread of obesity and insulin resistance increases the incidence of stroke. The direct effect of insulin resistance, as it pertains to stroke, on the central nervous system is not well understood. Since one of the physiological functions of the cellular prion protein (PrPC) is neuroprotection, we studied effects of brain insulin resistance on the expression of PrPC in fructose-fed rats as an animal model of prediabetes. Compared with control chow-fed animals, rats fed a high-fructose diet (FF), exhibited compromised tyrosine phosphorylation of insulin receptor β subunit (IRβ) and reduced serine phosphorylation of Akt, PI3K activity, and decreased PIP3 levels in cortices indicating the induction of brain insulin resistance. We also observed that both mRNA and protein expression of the PrPC was significantly decreased whereas protein level of NR2B subunit of NMDA glutamate receptors profoundly increased in the brain of fructose-fed rats compared to control chow-fed rats. Considering a neuroprotective role for PrPC and the involvement of NR2B subunit in the excitotoxicity-induced neuronal apoptosis, these phenomena may contribute to the severity and poor prognosis of ischemic stroke in diabetes/prediabetes.