Matrix Metalloprotease-9 Inhibition Improves Amyloid β-Mediated Cognitive Impairment and Neurotoxicity in Mice
Matrix Metalloprotease-9 Inhibition Improves Amyloid β-Mediated Cognitive Impairment and Neurotoxicity in Mice
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DOI：
10.1124/jpet.109.154724
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
--
作者：
Mizoguchi, Hiroyuki;Takuma, Kazuhiro;Yamada, Kiyofumi
在阿尔茨海默病（AD）中，能够降解细胞外基质蛋白的基质金属蛋白酶（MMPs）的表达在脑中增加。以往的研究表明，培养的胶质细胞的淀粉样β（A β）蛋白可以诱导MMP的表达，这可能参与A β的降解。在本研究中，我们研究了MMP-2和MMP-9在A β注射诱导的小鼠认知障碍中的作用。脑室内注射A β 25 - 35、A β 1 - 40和A β 1 - 42，但不注射A β 40 - 1，可短暂增加海马中MMP-9的活性和蛋白表达，但不增加MMP-2的活性和蛋白表达。免疫组化显示A β处理后海马神经元和胶质细胞中MMP-9的表达增加。在MMP-9纯合子敲除小鼠中以及通过MMP抑制剂治疗，A β诱导的体内认知障碍以及体外神经毒性显著减轻。这些结果表明，海马中MMP-9表达的增加参与了A β 1 - 40诱导的认知障碍的发展。因此，MMP-9的特异性抑制剂可能具有治疗AD的治疗潜力。我们的研究结果表明，与基于先前研究结果的预期相反，MMP-9在A β诱导的认知障碍和神经毒性中起着因果作用。
In Alzheimer's disease (AD), the expression of matrix metalloproteases (MMPs), which are capable of degrading extracellular matrix proteins, is increased in the brain. Previous studies with cultured glial cells have demonstrated that amyloid beta (A beta) protein can induce the expression of MMPs, which could be involved in the degradation of A beta. In the present study, we investigated the role of MMP-2 and MMP-9 in cognitive impairment induced by the injection of A beta in mice. The intracerebro-ventricular injection of A beta 25-35, A beta 1-40, and A beta 1-42, but not A beta 40-1, transiently increased MMP-9, but not MMP-2, activity and protein expression in the hippocampus. Immunohistochemistry revealed the expression of MMP-9 to be increased in both neurons and glial cells in the hippocampus after A beta treatment. The A beta-induced cognitive impairment in vivo as well as neurotoxicity in vitro was significantly alleviated in MMP-9 homozygous knockout mice and by treatment with MMP inhibitors. These results suggest the increase in MMP-9 expression in the hippocampus to be involved in the development of cognitive impairment induced by A beta 1-40. Thus, specific inhibitors of MMP-9 may have therapeutic potential for the treatment of AD. Our findings suggest that, as opposed to expectations based on previous findings, MMP-9 plays a causal role in A beta-induced cognitive impairment and neurotoxicity.