Protease nexin-2/amyloid β-protein precursor limits cerebral thrombosis

Abstract

The amyloid β-protein precursor (AβPP) is best known as the parent molecule to the amyloid β-peptide that accumulates in the brains of patients with Alzheimer9s disease. Secreted isoforms of AβPP that contain the Kunitz proteinase inhibitor domain are analogous to the previously identified cell-secreted proteinase inhibitor known as protease nexin-2 (PN2). Although PN2/AβPP is enriched in brain and in circulating blood platelets, little is understood of its physiological function and potential role in disease processes outside of amyloid β-peptide generation. We hypothesized that the potent inhibition of certain procoagulant proteinases by PN2/AβPP, coupled with its abundance in platelets and brain, indicate that it may function to regulate cerebral thrombosis. Here we show that specific and modest 2-fold overexpression of PN2/AβPP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2/AβPP in AβPP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2/AβPP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas AβPP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2/AβPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage.