MMP-7 cleaves amyloid β fragment peptides and copper ion inhibits the degradation
MMP-7 cleaves amyloid β fragment peptides and copper ion inhibits the degradation
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DOI：
10.1007/s10534-017-0048-4
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发表时间：
2017-09
期刊：
影响因子：
3.5
通讯作者：
Masanari Taniguchi;Kazuki Matsuura;Rina Nakamura;Aya Kojima;M. Konishi;T. Akizawa
中科院分区：
文献类型：
--
作者：
Masanari Taniguchi;Kazuki Matsuura;Rina Nakamura;Aya Kojima;M. Konishi;T. Akizawa
淀粉样蛋白β（Aβ）的细胞外沉积是阿尔茨海默病（AD）的根本原因。由淀粉样前体蛋白（APP）的β-分泌酶产生的Aβ1-42是神经炎斑块的主要成分，该蛋白的聚集在一定程度上依赖于金属离子，如铜和锌。然而，Cu 2+影响Aβ1-42或中枢神经系统理化性质的机制仍存在争议。近年来的一系列研究表明，可溶性基质金属蛋白酶（MMP-2和MMP-9）和膜型基质金属蛋白酶（MT 1-MMP）均能降解Aβ肽。MMP-7是一种可溶性基质金属蛋白酶，在海马组织中表达，但是，关于这种酶在阿尔茨海默病的过程和/或进展中的病理生理作用的信息较少。本研究检测了MMP-7对不同Aβ1-42片段肽段的降解活性以及Cu ~（2+）的影响。尽管Aβ22-40可被MMP-7降解（与Cu 2+无关），但Cu 2+可抑制MMP-7对Aβ1-19、Aβ11-20和Aβ11-29的降解。这些结果表明，MMP-7能够降解Aβ1-42，并且Aβ1-42通过Cu 2+结合和结构变化获得对MMP-7切割的抗性。我们的研究结果表明，MMP-7可能在抵抗Aβ1-42聚集的防御机制中发挥重要作用，Aβ1-42聚集导致AD的病理学改变。
The extracellular deposition of amyloid β (Aβ) is known to be the fundamental cause of Alzheimer’s disease (AD). Aβ1-42, generated by β-secretases from the amyloid precursor protein (APP), is the main component of neuritic plaque, and the aggregation of this protein is shown to be dependent to an extent on metal ions such as copper and zinc. However, the mechanism by which Cu2+affects the physicochemical properties of Aβ1-42 or the central nervous system is still under debate. A recent series of studies have demonstrated that both the soluble-type matrix metalloproteinases (MMP-2 and MMP-9) and the membrane-type matrix metalloproteinase (MT1-MMP) are capable of degrading Aβ peptides. MMP-7, one of the soluble-type matrix metalloproteinases, is expressed in hippocampal tissue; however, less information is available concerning the pathophysiological roles of this enzyme in the process and/or progress of Alzheimer’s disease. In this study, we examined the degradation activity of MMP-7 against various Aβ1-42’s fragment peptides and the effect of Cu2+. Although Aβ22-40 was degraded by MMP-7 regardless of Cu2+, Cu2+inhibited the degradation of Aβ1-19, Aβ11-20, and Aβ11-29 by MMP-7. These results indicate that MMP-7 is capable of degrading Aβ1-42, and that Aβ1-42 acquired resistance against MMP-7 cleavage through Cu2+-binding and structure changes. Our results demonstrate that MMP-7 may play an important role in the defensive mechanism against the aggregation of Aβ1-42, which gives rise to the pathology of AD.