Increased Severity of Hemorrhage in Transgenic Mice Expressing Cerebral Protease Nexin-2/Amyloid β-Protein Precursor

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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 3 [n=6; P P 3 [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.