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.
Xu
Feng
F
Department of Medicine, Stony Brook University, NY 11794, USA.
Davis
Judianne
J
Miao
Jianting
J
Previti
Mary Lou
ML
Romanov
Galina
G
Ziegler
Kelly
K
Van Nostrand
William E
WE
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D017931:DNA Primers; D015870:Gene Expression; D015151:Immunoblotting; D020767:Intracranial Thrombosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010314:Partial Thromboplastin Time; D015539:Platelet Activation / Q000502:physiology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D058255:Protease Nexins; D011956:Receptors, Cell Surface