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

Department of Medicine, Stony Brook University, Stony Brook, New York, United States
Stroke (Impact Factor: 5.72). 09/2007; 38(9):2598-601. DOI: 10.1161/STROKEAHA.106.480103
Source: PubMed


Secreted isoforms of amyloid beta-protein precursor (AbetaPP) 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/AbetaPP suggests that it may function to regulate cerebral thrombosis during vascular injury events.
To examine the antithrombotic function of cerebral PN2/AbetaPP in vivo, we performed measurements of carotid artery thrombosis and experimental intracerebral hemorrhage in transgenic mice with specific and modest overexpression of PN2/AbetaPP in brain. Comparisons were made with wild-type mice and Tg-rPF4/APP mice, a model that possesses specific and modest overexpression of PN2/AbetaPP in platelets and exhibits reduced thrombosis in vivo.
Modest overexpression of PN2/AbetaPP 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<0.01] and 1411+/-202 microg/hemisphere [n=12; P<0.01], respectively), compared with wild-type mice (15.9+/-2.2 mm(3) [n=6] and 935+/-418 microg/hemisphere [n=12], respectively).
These findings indicate that cerebral PN2/AbetaPP 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.

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    • "The role of APP in platelet is currently unclear. It has been proposed that soluble APP fragments may regulate thrombosis and haemostasis in vivo through the Kunitz proteinase inhibitor domain [10], and that a pool of APP soluble fragments is stored in platelet α-granules and is released upon platelet stimulation with several agonists [8]. The proteolytic processing of APP on the platelet surface shares some common feature with the well-described shedding of extracellular domains of some platelet receptors, including the collagen receptor GPVI, the GPIbα and GPV subunits of the von Willebrand factor receptor GPIb-IX-V complex, and the inhibitory receptor PECAM-1 [11]. "
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