Potential role of protease nexin-2/amyloid beta-protein precursor as a cerebral anticoagulant

The amyloid beta-protein precursor (APP) is the parent molecule to the amyloid beta-protein which is a major constituent of neuritic plaques and cerebrovascular deposits in Alzheimer's disease (AD). The protease inhibitor, protease nexin-2 (PN-2), is the secreted form of APP that contains the Kunitz protease inhibitor (KPI) domain. We reported that the predominant isoform of APP in human brain contains the KPI domain and is thus PN-2. Quantitation of PN-2/APP in various tissues revealed that it is primarily found in brain. Circulating blood platelets are another rich source of PN-2/APP. Platelet PN-2/APP is contained in platelet alpha granules and is secreted upon activation of platelets by physiological agonists. Protease inhibition measurements demonstrated that PN-2/APP is a potent inhibitor of intrinsic blood coagulation factor XIa. These findings suggest that PN-2/APP may play a role in the regulation of blood coagulation and platelets may serve as a systemic vehicle to deliver large amounts of this protein to sites of vascular injury. In addition, we propose that the rich, and relatively exclusive, investment of PN-2/APP in brain suggests that it may function locally as an intracerebral anticoagulant.