DOI: 10.1161/01.str.0000217262.03192.d4. Deletion of Cellular Prion Protein Results in Reduced Akt Activation, Enhanced Postischemic Caspase-3 Activation, and Exacerbation of Ischemic Brain Injury

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

10.1161/01.str.0000217262.03192.d4

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Stroke (276)

Abstract

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 mm 3 ; 119.8±24 versus 86.4±25 mm 3 ). 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.

Bibliography

Weise, J., Sandau, R., Schwarting, S., Crome, O., Wrede, A., Schulz-Schaeffer, W., Zerr, I., & BaÌhr, M. (2006). Deletion of Cellular Prion Protein Results in Reduced Akt Activation, Enhanced Postischemic Caspase-3 Activation, and Exacerbation of Ischemic Brain Injury. Stroke, 37(5), 1296â1300.

Authors 8

Jens Weise (first)
Raoul Sandau (additional)
Sönke Schwarting (additional)
Olaf Crome (additional)
Arne Wrede (additional)
Walter Schulz-Schaeffer (additional)
Inga Zerr (additional)
Mathias Bähr (additional)

References 26 Referenced 133

Dates

Type	When
Created	19 years, 5 months ago (March 30, 2006, 8:59 p.m.)
Deposited	1 year, 3 months ago (May 12, 2024, 5:31 p.m.)
Indexed	3 days, 13 hours ago (Sept. 3, 2025, 6:43 a.m.)
Issued	19 years, 4 months ago (May 1, 2006)
Published	19 years, 4 months ago (May 1, 2006)
Published Print	19 years, 4 months ago (May 1, 2006)

Funders 0

None

BibTeX

@article{Weise_2006, title={Deletion of Cellular Prion Protein Results in Reduced Akt Activation, Enhanced Postischemic Caspase-3 Activation, and Exacerbation of Ischemic Brain Injury}, volume={37}, ISSN={1524-4628}, url={http://dx.doi.org/10.1161/01.str.0000217262.03192.d4}, DOI={10.1161/01.str.0000217262.03192.d4}, number={5}, journal={Stroke}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Weise, Jens and Sandau, Raoul and Schwarting, Sönke and Crome, Olaf and Wrede, Arne and Schulz-Schaeffer, Walter and Zerr, Inga and Bähr, Mathias}, year={2006}, month=may, pages={1296–1300} }

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  "abstract": "<jats:p>\n            <jats:bold>\n              <jats:italic>Background and Purpose\u2014</jats:italic>\n            </jats:bold>\n            The physiological function of cellular prion protein (PrP\n            <jats:sup>c</jats:sup>\n            ) is not yet understood. Recent findings suggest that PrP\n            <jats:sup>c</jats:sup>\n            may have neuroprotective properties, and its absence increases susceptibility to neuronal injury. The purpose of this study was to elucidate the role of PrP\n            <jats:sup>c</jats:sup>\n            in ischemic brain injury in vivo.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods\u2014</jats:italic>\n            </jats:bold>\n            PrP knockout (Prnp\n            <jats:sup>0/0</jats:sup>\n            ) and Prnp\n            <jats:sup>+/+</jats:sup>\n            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\n            <jats:sup>c</jats:sup>\n            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.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Results\u2014</jats:italic>\n            </jats:bold>\n            Prnp\n            <jats:sup>0/0</jats:sup>\n            mice displayed significantly increased infarct volumes after both transient or permanent ischemia when compared with WT animals (70.2\u00b123 versus 13.3\u00b14 mm\n            <jats:sup>3</jats:sup>\n            ; 119.8\u00b124 versus 86.4\u00b125 mm\n            <jats:sup>3</jats:sup>\n            ). Expression of phospho-Akt (Ser473) was significantly reduced in Prnp\n            <jats:sup>0/0</jats:sup>\n            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\n            <jats:sup>0/0</jats:sup>\n            mice. In contrast, expression of total Akt, Bax, and Bcl-2 did not differ between both groups.\n          </jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014</jats:italic>\n            </jats:bold>\n            These results demonstrate that PrP\n            <jats:sup>c</jats:sup>\n            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.\n          </jats:p>",
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