Szklarczyk A, Conant K, Owens D F, Ravin R, McKay R D, Gerfen C
Laboratory of Systems Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Neuroscience. 2007 Oct 12;149(1):87-98. doi: 10.1016/j.neuroscience.2007.07.032. Epub 2007 Jul 28.
Matrix metalloproteinase-7 (MMP-7) belongs to a family of zinc dependent endopeptidases that are expressed in a variety of tissues including the brain. MMPs are known to be potent mediators of pericellular proteolysis and likely mediators of dynamic remodelling of neuronal connections. While an association between proteases and the neuronal synapse is emerging, a full understanding of this relationship is lacking. Here, we show that MMP-7 alters the structure and function of presynaptic terminals without affecting neuronal survival. Bath application of recombinant MMP-7 to cultured rat neurons induced long-lasting inhibition of vesicular recycling as measured by synaptotagmin 1 antibody uptake assays and FM4-64 optical imaging. MMP-7 application resulted in reduced abundance of vesicular and active zone proteins locally within synaptic terminals although their general levels remained unaltered. Finally, chronic application of the protease resulted in synaptic atrophy, including smaller terminals and fewer synaptic vesicles, as determined by electron microscopy. Together these results suggest that MMP-7 is a potent modulator of synaptic vesicle recycling and synaptic ultrastructure and that elevated levels of the enzyme, as may occur with brain inflammation, may adversely influence neurotransmission.
基质金属蛋白酶-7（MMP-7）属于锌依赖性内肽酶家族，在包括大脑在内的多种组织中表达。已知MMPs是细胞周围蛋白水解的有效介质，可能是神经元连接动态重塑的介质。虽然蛋白酶与神经元突触之间的关联正在显现，但对这种关系仍缺乏全面的了解。在这里，我们表明MMP-7改变突触前终末的结构和功能，而不影响神经元存活。通过突触结合蛋白1抗体摄取试验和FM4-64光学成像测量，将重组MMP-7浴应用于培养的大鼠神经元可诱导囊泡循环的长期抑制。应用MMP-7导致突触终末内局部囊泡和活性区蛋白丰度降低，尽管它们的总体水平保持不变。最后，通过电子显微镜确定，长期应用该蛋白酶导致突触萎缩，包括终末变小和突触囊泡减少。这些结果共同表明，MMP-7是突触囊泡循环和突触超微结构的有效调节剂，并且该酶水平升高（如在脑部炎症时可能发生的情况）可能对神经传递产生不利影响。
