Overexpression of cellular prion protein alters postischemic Erk1/2 phosphorylation but not Akt phosphorylation and protects against focal cerebral ischemia

Abstract

Purpose: The physiological function of the cellular prion protein (PrP(C)) is still unclear. A growing body of evidence suggests that PrP(C) has neuroprotective properties and that its deletion increases susceptibility to focal cerebral ischemia. The purpose of this study was to elucidate the role of PrP(C) overexpression in ischemic brain injury in vivo. Methods: PrP(C) overexpressing (TG35) and wild type (WT) mice were subjected to a 90-minute transient focal cerebral ischemia followed by infarct volume analysis 24 hours after lesion. To identify effects of PrP(C) overexpression on signalling pathways important for the regulation of ischemic cell death, we studied postischemic activation and expression of Akt and Erk1/2 using quantitative Western Blot analysis. Results: TG35 mice displayed significantly smaller infarct volumes and showed reduced early postischemic Erk1/2 phosphorylation, a pathway known to exacerbate neuronal injury following transient cerebral ischemia. In contrast, PrP(C) overexpression did not change postischemic Akt phosphorylation, which acts anti-apoptotic and is reduced in PrP(C) knockout animals. Conclusions: These results demonstrate that PrP(C) overexpression reduces deleterious Erk1/2 activation but does not affect Akt activation after transient cerebral ischemia, suggesting a role for distinct cytosolic signalling pathways in PrP(C) mediated neuroprotection.