MMP-7 cleaves amyloid β fragment peptides and copper ion inhibits the degradation

The extracellular deposition of amyloid beta (A beta) is known to be the fundamental cause of Alzheimer's disease (AD). A beta 1-42, generated by beta-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 A beta 1-42 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 A beta 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 A beta 1-42's fragment peptides and the effect of Cu2+. Although A beta 22-40 was degraded by MMP-7 regardless of Cu2+, Cu2+ inhibited the degradation of A beta 1-19, A beta 11-20, and A beta 11-29 by MMP-7. These results indicate that MMP-7 is capable of degrading A beta 1-42, and that A beta 1-42 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 A beta 1-42, which gives rise to the pathology of AD.