Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis.
The amyloid beta-protein precursor (AbetaPP) is best known as the parent molecule to the amyloid beta-peptide that accumulates in the brains of patients with Alzheimer's disease. Secreted isoforms of AbetaPP 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/AbetaPP 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 beta-peptide generation. We hypothesized that the potent inhibition of certain procoagulant proteinases by PN2/AbetaPP, 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/AbetaPP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2/AbetaPP in AbetaPP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2/AbetaPP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas AbetaPP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2/AbetaPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage.[1]References
- Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosis. Xu, F., Davis, J., Miao, J., Previti, M.L., Romanov, G., Ziegler, K., Van Nostrand, W.E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
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