Institute of Pathobiochemistry, University Medical Centre of the Johannes Gutenberg University of Mainz, 55128 Mainz, Germany.
J Biol Chem. 2012 Sep 28;287(40):33304-13. doi: 10.1074/jbc.M112.395608. Epub 2012 Aug 9.
The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin β cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin β can also process APP in a manner reminiscent of β-secretase. We identified cleavage sites of meprin β in the amyloid β sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating Aβ variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin β than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin β on APP and Aβ generation was also observed in the absence of BACE1/2 activity using a β-secretase inhibitor and BACE knock-out cells, indicating that meprin β acts independently of β-secretase.
淀粉样蛋白 β（Aβ）肽在患有阿尔茨海默病患者的大脑中大量存在，是该疾病发病机制的核心。因此，了解淀粉样前体蛋白（APP）的加工过程至关重要。最近，我们证明金属蛋白酶 meprin β 可切割 APP 并释放可溶性 N 端 APP（N-APP）片段。在这项工作中，我们提供了证据表明，mepr in β 可以以类似于β-分泌酶的方式处理 APP。我们在 APP 的野生型和瑞典突变型的淀粉样蛋白 β 序列中鉴定了 meprin β 的切割位点，位于 p1 和 p2 位置，从而生成从第一个或第二个氨基酸残基开始的 Aβ 变体。我们观察到，对于野生型和瑞典突变型 APP 形式，mepr in β 的酶动力学值均高于 BACE1。在使用β-分泌酶抑制剂和 BACE 敲除细胞排除 BACE1/2 活性的情况下，也观察到了 meprin β 在 APP 和 Aβ 生成上的这种酶活性，表明 meprin β 独立于β-分泌酶发挥作用。
