Published Online
on March 30, 2006

A more recent version of this article appeared on May 1, 2006

This Article Full Text (PDF) All Versions of this Article: 37/5/1296    most recent 01.STR.0000217262.03192.d4v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Weise, J. Articles by Bähr, M. Search for Related Content PubMed PubMed Citation Articles by Weise, J. Articles by Bähr, M. Related Collections Animal models of human disease Apoptosis

Submitted on December 2, 2005
Revised on February 3, 2006
Accepted on February 8, 2006

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; and 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.

^* To whom correspondence should be addressed. 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

This article has been cited by other articles:

				H. Khosravani, Y. Zhang, S. Tsutsui, S. Hameed, C. Altier, J. Hamid, L. Chen, M. Villemaire, Z. Ali, F. R. Jirik, et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors J. Cell Biol., October 14, 2008; 181(3): 551 - 565. [Abstract] [Full Text] [PDF]

				S. Tsutsui, J. N. Hahn, T. A. Johnson, Z. Ali, and F. R. Jirik Absence of the Cellular Prion Protein Exacerbates and Prolongs Neuroinflammation in Experimental Autoimmune Encephalomyelitis Am. J. Pathol., October 1, 2008; 173(4): 1029 - 1041. [Abstract] [Full Text] [PDF]

				R. Linden, V. R. Martins, M. A. M. Prado, M. Cammarota, I. Izquierdo, and R. R. Brentani Physiology of the Prion Protein Physiol Rev, April 1, 2008; 88(2): 673 - 728. [Abstract] [Full Text] [PDF]

				K.-J. Lee, A. Panzera, D. Rogawski, L. E. Greene, and E. Eisenberg Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation J. Cell Sci., August 1, 2007; 120(15): 2663 - 2671. [Abstract] [Full Text] [PDF]