Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursor.

Stroke (Impact Factor: 6.16). 09/2007; 38(9):2598-601. DOI: 10.1161/STROKEAHA.106.480103
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Blood-based tests for a rapid and valid diagnosis as well as outcome prognosis of acute stroke are desirable. Recently, plasma Aβ40 was suggested as an independent cerebrovascular risk factor candidate. We investigated eight plasma samples of patients with clinical signs of acute cerebral ischemia for derangements of plasma amyloid-beta (Aβ) peptide patterns as compared to 13 patients with other neuropsychiatric diseases. For the analysis of plasma, we used immunoprecipitation followed by the quantitative Aβ-SDS-PAGE/immunoblot. The major outcome was a striking decrease of Aβ1-40 in plasma paralleled by an increase in the ratio of Aβ1-38/Aβ1-40 in two patients with acute stroke. Interestingly, these patients had an onset of symptoms within only 2-4 hr before venous puncture and there was a strong correlation of Aβ1-38/Aβ1-40 levels with the time span between onset of symptoms and venous puncture. From these results, we suggest the ratio of plasma Aβ1-38/Aβ1-40 as a possible biomarker for the early diagnosis of acute stroke.
    Journal of Clinical Laboratory Analysis 07/2012; 26(4):238-45. · 1.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Coagulation factor XI (FXI) plays an important part in both venous and arterial thrombosis, rendering FXIa a potential target for the development of antithrombotic therapy. The kunitz protease inhibitor (KPI) domain of protease nexin-2 (PN2) is a potent, highly specific inhibitor of FXIa, suggesting its possible role in the inhibition of FXI-dependent thrombosis in vivo. Therefore, we examined the effect of PN2KPI on thrombosis in the murine carotid artery and the middle cerebral artery. Intravenous administration of PN2KPI prolonged the clotting time of both human and murine plasma, and PN2KPI inhibited FXIa activity in both human and murine plasma in vitro. The intravenous administration of PN2KPI into WT mice dramatically decreased the progress of FeCl(3)-induced thrombus formation in the carotid artery. After a similar initial rate of thrombus formation with and without PN2KPI treatment, the propagation of thrombus formation after 10 minutes and the amount of thrombus formed were significantly decreased in mice treated with PN2KPI injection compared with untreated mice. In the middle cerebral artery occlusion model, the volume and fraction of ischemic brain tissue were significantly decreased in PN2KPI-treated compared with untreated mice. Thus, inhibition of FXIa by PN2KPI is a promising approach to antithrombotic therapy.
    Blood 06/2012; 120(3):671-7. · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The β-amyloid precursor protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) of Alzheimer's disease. However, the normal function of APP remains largely unknown. This article reviews studies on the structure, expression and post-translational processing of APP, as well as studies on the effects of APP in vitro and in vivo. We conclude that the published data provide strong evidence that APP has a trophic function. APP is likely to be involved in neural stem cell development, neuronal survival, neurite outgrowth and neurorepair. However, the mechanisms by which APP exerts its actions remain to be elucidated. The available evidence suggests that APP interacts both intracellularly and extracellularly to regulate various signal transduction mechanisms. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2014; · 3.97 Impact Factor