Deletion of cellular prion protein results in reduced Akt activation, enhanced postischemic caspase-3 activation, and exacerbation of ischemic brain injury.

Background And Purpose: The physiological function of cellular prion protein (PrPc) is not yet understood. Recent findings suggest that PrPc may have neuroprotective properties, and its absence increases susceptibility to neuronal injury. The purpose of this study was to elucidate the role of PrPc in ischemic brain injury in vivo.

Methods: PrP knockout (Prnp(0/0)) and Prnp(+/+) wild-type (WT) mice were subjected to 60-minute transient or permanent focal cerebral ischemia followed by infarct volume analysis 24 hours after lesion. To identify effects of PrPc deletion on mechanisms regulating ischemic cell death, expression analysis of several proapoptotic and antiapoptotic proteins was performed at 6 and 24 hours after transient ischemia and in nonischemic controls using Western blot or immunohistochemistry.

Results: Prnp(0/0) mice displayed significantly increased infarct volumes after both transient or permanent ischemia when compared with WT animals (70.2+/-23 versus 13.3+/-4 mm3; 119.8+/-24 versus 86.4+/-25 mm3). Expression of phospho-Akt (Ser473) was significantly reduced in Prnp(0/0) compared with WT animals both early after ischemia and in sham controls. Furthermore, postischemic caspase-3 activation was significantly enhanced in the basal ganglia and the parietal cortex of Prnp(0/0) mice. In contrast, expression of total Akt, Bax, and Bcl-2 did not differ between both groups.

Conclusions: These results demonstrate that PrPc deletion impairs the antiapoptotic phosphatidylinositol 3-kinase/Akt pathway by resulting in reduced postischemic phospho-Akt expression, followed by enhanced postischemic caspase-3 activation, and aggravated neuronal injury after transient and permanent cerebral ischemia.