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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Protease nexin-2/amyloid β-protein precursor limits cerebral thrombosis
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Protease nexin-2/amyloid β-protein precursor limits cerebral thrombosis

机译：蛋白酶nexin-2 /淀粉样β蛋白前体可限制脑血栓形成

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摘要

The amyloid β-protein precursor (AβPP) is best known as the parent molecule to the amyloid β-peptide that accumulates in the brains of patients with Alzheimer's disease. Secreted isoforms of AβPP 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/AβPP 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 β-peptide generation. We hypothesized that the potent inhibition of certain procoagulant protein-ases by PN2 AβPP, 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/AβPP in circulating platelets of transgenic mice caused a marked inhibition of thrombosis in vivo. In contrast, deletion of PN2/AβPP in AβPP gene knockout mice resulted in a significant increase in thrombosis. Similarly, platelet PN2/AβPP transgenic mice developed larger hematomas in experimental intracerebral hemorrhage, whereas AβPP gene knockout mice exhibited reduced hemorrhage size. These findings indicate that PN2/AβPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage.
机译：淀粉样蛋白β蛋白前体（AβPP）最著名的是淀粉样蛋白β肽的亲本分子，该蛋白在阿尔茨海默氏病患者的大脑中积累。包含Kunitz蛋白酶抑制剂结构域的AβPP的分泌同工型类似于先前鉴定的称为蛋白酶nexin-2（PN2）的细胞分泌的蛋白酶抑制剂。尽管PN2 /AβPP富含脑和循环血小板，但对其生理功能以及在淀粉样β肽生成之外的疾病过程中的潜在作用了解甚少。我们假设PN2AβPP对某些促凝蛋白酶的有效抑制作用，以及其在血小板和脑中的丰度，表明它可能起到调节脑血栓形成的作用。在这里，我们显示在转基因小鼠的循环血小板中PN2 /AβPP的特异性和适度2倍过表达在体内引起血栓形成的明显抑制。相反，在AβPP基因敲除小鼠中PN2 /AβPP的缺失导致血栓形成的显着增加。同样，在实验性脑出血中，血小板PN2 /AβPP转基因小鼠发生较大的血肿，而基因敲除AβPP基因的小鼠出血量减少。这些发现表明，PN2 /AβPP在调节脑血栓形成中起着重要作用，并且该蛋白的适度增加可以深刻地增强脑出血。

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