Timp-3 deficiency impairs cognitive function in mice
Timp-3 deficiency impairs cognitive function in mice
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DOI：
10.1038/labinvest.2009.101
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发表时间：
2009-12-01
影响因子：
5
通讯作者：
Rakugi, Hiromi
中科院分区：
文献类型：
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作者：
Baba, Yoshichika;Yasuda, Osamu;Rakugi, Hiromi
细胞外基质（ECM）降解主要由基质金属蛋白酶（MMP）进行。MMPs最近被证明可以调节海马中的突触活动并影响记忆和学习。金属蛋白酶组织抑制剂（TIMP）是一种内源性因子，通过结合到MMP的催化位点来控制MMP的活性。目前，已经报道了四种Timp同种型（Timp-1至Timp-4），具有35-50%的氨基酸序列同源性。Timp-3是Timp蛋白的独特成员，因为它与ECM结合。本研究采用被动回避实验、主动回避实验和水迷宫实验检测Timp-3基因敲除小鼠的认知功能。使用旷场试验评价习惯性。水迷宫测试显示，与野生型（WT）小鼠相比，Timp-3 KO小鼠表现出认知功能的恶化。旷场试验显示Timp-3 KO小鼠的习惯性降低。脑切片免疫组化染色显示海马区有TIMP-3的表达。海马的原位酶谱显示与WT小鼠相比，Timp-3 KO小鼠的明胶分解活性增加。这些结果提供了小鼠中Timp-3参与认知功能和海马MMP活性的第一证据。此外，我们的研究结果表明，一个新的治疗目标，以探索改善人类的认知功能。实验室调查（2009）89，1340-1347; doi：10.1038/labinvest.2009.101; 2009年10月5日在线发表
Extracellular matrix (ECM) degradation is performed primarily by matrix metalloproteinases (MMPs). MMPs have recently been shown to regulate synaptic activity in the hippocampus and to affect memory and learning. The tissue inhibitor of metalloproteinase (Timp) is an endogenous factor that controls MMP activity by binding to the catalytic site of MMPs. At present, four Timp isotypes have been reported (Timp-1 through Timp-4) with 35-50% amino-acid sequence homology. Timp-3 is a unique member of Timp proteins in that it is bound to the ECM. In this study, we used the passive avoidance test, active avoidance test, and water maze test to examine the cognitive function in Timp-3 knockout (KO) mice. Habituation was evaluated using the open-field test. The water maze test showed that Timp-3 KO mice exhibit deterioration in cognitive function compared with wild-type (WT) mice. The open-field test showed decreased habituation of Timp-3 KO mice. Immunostaining of brain slices revealed the expression of Timp-3 in the hippocampus. In situ zymography of the hippocampus showed increased gelatinolytic activity in Timp-3 KO mice compared with WT mice. These results present the first evidence of Timp-3 involvement in cognitive function and hippocampal MMP activity in mice. Moreover, our findings suggest a novel therapeutic target to be explored for improvement of cognitive function in humans. Laboratory Investigation (2009) 89, 1340-1347; doi:10.1038/labinvest.2009.101; published online 5 October 2009