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(Stroke. 2006;37:1296.)
© 2006 American Heart Association, Inc.

Original Contributions

Deletion of Cellular Prion Protein Results in Reduced Akt Activation, Enhanced Postischemic Caspase-3 Activation, and Exacerbation of Ischemic Brain Injury

Jens Weise, MD; Raoul Sandau, MD; Sönke Schwarting, MD; Olaf Crome, MD; Arne Wrede, MD; Walter Schulz-Schaeffer, MD; Inga Zerr, MD Mathias Bähr, MD

From the Departments of Neurology (J.W., R.S., S.S., O.C., I.Z., M.B.) and Neuropathology (A.W., W.S.-S.), University of Goettingen Medical School, Germany.

Correspondence to Jens Weise, MD, Department of Neurology, University of Goettingen Medical School, Robert-Koch-Str. 40, 37075 Goettingen, Germany. E-mail jweise{at}gwdg.de

Background and Purpose— The physiological function of cellular prion protein (PrP^c) is not yet understood. Recent findings suggest that PrP^c may have neuroprotective properties, and its absence increases susceptibility to neuronal injury. The purpose of this study was to elucidate the role of PrP^c 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 PrP^c 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 PrP^c 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.

Key Words: caspases • cerebral ischemia • PrP^c proteins • signal transduction

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