Enhanced neuronal plasticity and elevated endogenous sAPPa levels in mice over-expressing MMP9
Enhanced neuronal plasticity and elevated endogenous sAPPa levels in mice over-expressing MMP9
复制标题
DOI：
10.1111/j.1471-4159.2011.07637.x
复制
发表时间：
2012-04-01
影响因子：
4.7
通讯作者：
Tzinia, Athina K.
中科院分区：
文献类型：
--
作者：
Fragkouli, Apostolia;Papatheodoropoulos, Costas;Tzinia, Athina K.
在过去的几年中，越来越多的证据表明基质金属蛋白酶9（MMP 9）的酶活性在突触可塑性和认知过程中发挥着重要作用。我们先前已经证明，MMP 9参与受体介导的α-分泌酶样APP体外裂解，导致sAPPa分泌增加，sAPPa是已知参与神经元可塑性和记忆形成的非淀粉样蛋白生成途径的可溶性N-末端产物。为了研究MMP 9在体内的作用，我们已经产生了在大脑中过表达MMP 9的转基因小鼠。在此，我们证明，MMP 9转基因动物显示增强的性能在非空间新的物体识别和空间水迷宫任务，其增强的性能是伴随着增加的树突棘密度在海马和皮层以下的行为测试。与上述观察结果一致，电生理学分析揭示了MMP 9转基因小鼠海马切片中长时程突触增强的长期维持。此外，还观察到MPP 9转基因动物的海马和皮质中sAPPa水平升高。总之，我们的研究结果扩展了先前关于MMP 9在神经元可塑性中的生理作用的发现，并且进一步揭示，APP可能是MMP 9在体内的生理性蛋白水解靶点之一。
Evidence accumulating during the past few years points to a significant role of matrix metalloproteinase 9 (MMP9) enzymatic activity in synaptic plasticity and cognitive processes. We have previously demonstrated that MMP9 is involved in receptor-mediated a-secretase-like cleavage of APP in vitro, resulting in increased secretion of sAPPa, the soluble N-terminal product of the non-amyloidogenic pathway known to be involved in neuronal plasticity and memory formation. To study the in vivo role of MMP9, we have generated transgenic mice over-expressing MMP9 in the brain. Herein, we demonstrate that MMP9 transgenic animals display enhanced performance in the non-spatial novel object recognition and the spatial water-maze task and that their enhanced performance was accompanied by increased dendritic spine density in the hippocampus and cortex following behavioural testing. Consistent with the above observations, the electrophysiological analysis revealed prolonged maintenance of long-term synaptic potentiation in hippocampal slices from MMP9 transgenic mice. Moreover, elevated sAPPa levels in the hippocampus and cortex of MPP9 transgenic animals were also observed. Overall, our results extend previous findings on the physiological role of MMP9 in neuronal plasticity and furthermore reveal that, APP may be one of the physiological proteolytic targets of MMP9 in vivo.