AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis.

Abstract	The amyloid beta-protein precursor (AbetaPP) is best recognized as the precursor to the Abeta peptide that accumulates in the brains of patients with Alzheimer's disease, but less is known about its physiological functions. Isoforms of AbetaPP that contain a Kunitz-type serine proteinase inhibitor (KPI) domain are expressed in brain and, outside the CNS, in circulating blood platelets. Recently, we showed that KPI-containing forms of AbetaPP regulates cerebral thrombosis in vivo (Xu et al., 2005, 2007). Amyloid precursor like protein-2 (APLP2), a closely related homolog to AbetaPP, also possesses a highly conserved KPI domain. Virtually nothing is known of its function. Here, we show that APLP2 also regulates cerebral thrombosis risk. Recombinant purified KPI domains of AbetaPP and APLP2 both inhibit the plasma clotting in vitro. In a carotid artery thrombosis model, both AbetaPP(-/-) and APLP2(-/-) mice exhibit similar significantly shorter times to vessel occlusion compared with wild-type mice indicating a prothrombotic phenotype. Similarly, in an experimental model of intracerebral hemorrhage, both AbetaPP(-/-) and APLP2(-/-) mice produce significantly smaller hematomas with reduced brain hemoglobin content compared with wild-type mice. Together, these results indicate that AbetaPP and APLP2 share overlapping anticoagulant functions with regard to regulating thrombosis after cerebral vascular injury.
Authors	Feng Xu, Mary Lou Previti, Marvin T Nieman, Judianne Davis, Alvin H Schmaier, William E Van Nostrand
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 17 Pg. 5666-70 (Apr 29 2009) ISSN: 1529-2401 [Electronic] United States
PMID	19403832 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Amyloid beta-Protein Precursor Aplp2 protein, mouse Aprotinin
Topics	Amyloid beta-Protein Precursor (genetics, physiology) Animals Aprotinin (genetics, physiology) Blood Coagulation (genetics, physiology) Humans Intracranial Thrombosis (enzymology, metabolism) Mice Mice, Inbred C57BL Mice, Knockout Multigene Family Risk Factors

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