Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid β-protein precursor

Abstract

BACKGROUND AND PURPOSE - Secreted isoforms of amyloid β-protein precursor (AβPP) that contain the Kunitz proteinase inhibitor domain, also known as protease nexin-2 (PN2), are enriched in brain. Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/AβPP suggests that it may function to regulate cerebral thrombosis during vascular injury events. METHODS - To examine the antithrombotic function of cerebral PN2/AβPP in vivo, we performed measurements of carotid artery thrombosis and experimental intracerebral hemorrhage in transgenic mice with specific and modest overexpression of PN2/AβPP in brain. Comparisons were made with wild-type mice and Tg-rPF4/APP mice, a model that possesses specific and modest overexpression of PN2/AβPP in platelets and exhibits reduced thrombosis in vivo. RESULTS - Modest overexpression of PN2/AβPP in transgenic mouse brain had no effect on intraluminal carotid arterial thrombosis but resulted in larger hematoma volumes and hemoglobin levels (23.1±2.7 mm [n=6; P<0.01] and 1411±202 μg/hemisphere [n=12; P<0.01], respectively), compared with wild-type mice (15.9±2.2 mm [n=6] and 935±418 μg/hemisphere [n=12], respectively). CONCLUSIONS - These findings indicate that cerebral PN2/AβPP plays a significant role in regulating thrombosis in brain and that modest age-related increases in the cerebral levels of this protein could markedly enhance the extent of cerebral hemorrhage. © 2007 American Heart Association, Inc.