AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis.
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.
Xu
Feng
F
Department of Medicine, Stony Brook University, Stony Brook, New York 11794-8153, USA.
Previti
Mary Lou
ML
Nieman
Marvin T
MT
Davis
Judianne
J
Schmaier
Alvin H
AH
Van Nostrand
William E
WE
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D007611:Aprotinin / Q000235:genetics / Q000502:physiology*; D001777:Blood Coagulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D020767:Intracranial Thrombosis / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family; D012307:Risk Factors
D016564:Amyloid beta-Protein Precursor; C492952:Aplp2 protein, mouse; D007611:Aprotinin