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The Journal of Neuroscience, September 28, 2005, 25(39):8967-8977; doi:10.1523/JNEUROSCI.1115-05.2005

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Neurobiology of Disease
Overexpression of PrP^C by Adenovirus-Mediated Gene Targeting Reduces Ischemic Injury in a Stroke Rat Model

Woei-Cherng Shyu,^1 * Shinn-Zong Lin,^1 * Ming-Fu Chiang,² Dah-Ching Ding,¹ Kuo-Wei Li,¹ Shih-Fen Chen,¹ Hui-I Yang,¹ and Hung Li^3,4

¹Department of Neurology, Neuro-Medical Scientific Center, Tzu-Chi Buddhist General Hospital, Tzu-Chi University, Hualien, Taiwan 970, ²Department of Neurosurgery, Mackay Memorial Hospital, Mackay Junior College of Nursing, Taipei, Taiwan 112, ³Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 115, and ⁴Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan 112

Prion diseases are induced by pathologically misfolded prion protein (PrP^Sc), which recruit normal sialoglycoprotein PrP^C by a template-directed process. In this study, we investigated the expression of PrP^C in a rat model of cerebral ischemia to more fully understand its physiological role. Immunohistochemical analysis demonstrated that PrP^C-immunoreactive cells increased significantly in the penumbra of ischemic rat brain compared with the untreated brain. Western blot analysis showed that PrP^C protein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrP^C protein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrP^C by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrP^C-Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrP^C in the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrP^C and activated extracellular signal-regulated kinase (ERK1/2) under hypoxia–reoxygenation in primary cortical cultures was shown to be dependent on ERK1/2 phosphorylation. During hypoxia–reoxygenation, mouse neuroblastoma cell line N18 cells transfected with luciferase rat PrP^C promoter reporter constructs, containing the heat shock element (HSE), expressed higher luciferase activities (3- to 10-fold) than those cells transfected with constructs not containing HSE. We propose that HSTF-1 (hypoxia-activated transcription factor), phosphorylated by ERK1/2, may in turn interact with HSE in the promoter of PrP^C resulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrP^C expression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrP^C has physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia.

Key words: prion protein (PrP^C); stress protein; cerebral ischemia animal model; hypoxia–reoxygenation; primary cortical neurons; neuroprotection

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Received Dec 20, 2004; revised June 10, 2005; accepted August 2, 2005.

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