AbstractThe physiologic properties of the normal cellular prion protein (PrPC) have not been established fully, although recent evidence showed its upregulation in cerebral ischaemia. Using patients, animal models, and in vitro studies we aimed to identify in detail the expression and localization of PrPC in ischemic stroke. Patients in acute phase of ischaemic stroke had increased plasma levels of circulating PrPC as compared to healthy age‐ and gender‐matched controls (3.1 ± 1.4 vs. 1.9 ± 0.7 ng/ml, P = 0.002). Immunohistochemistry showed increased expression of PrPC in the soma of peri‐infarcted neurones as well as in the endothelial cells (EC) of micro‐vessels and inflammatory cells in peri‐infarcted brain tissue from patients who survived for 2–34 days after an initial stroke. The same pattern was repeated 1–48 hr after MCAO. RT‐PCR showed increased gene expression of PrPC by human foetal neurons (HFN) after 12 hr of oxygen glucose deprivation (OGD), which remained increased after 24 hr reperfusion. Western blotting confirmed that protein expression was similarly upregulated, and fluorescent labeling showed a notable increase in peri‐nuclear and axonal PrPC staining intensity. Increased plasma PrPC seems to reflect endogenous expression in acute stroke‐affected brain tissue. Increased cellular expression in peri‐infarcted regions may influence hypoxia‐induced cell damage, although the effects on EC survival and angiogenesis remain to be elucidated. © 2006 Wiley‐Liss, Inc.