miR132-Mecp2信号通路在AD样学习记忆损伤中的机制研究。

MiR132 is enriched in nerve tissue, including the hippocampus and cortex, and specifically expressed in the neurons. The miR132 level is downregulation in some neurodegeneration disease associated with learning and memory impairment including Huntington’s disease, schizophrenia and Alzheimer’s disease. Preliminary results show that the expression of miR132 in hippocampus and cortex of Tg2576 mice significantly decreased compared with the adult mice. Accompanied with a reduction of synapse-associated protein PSD95, NR2B, GluR1. The results of Morris Water Maze、Step Down、Fear Conditioning show that mice injected by LNA-miR132[miR132 Inhibitor] have a serious impairment of learning and memory compared with mice injected by LNA-Scramble[Control]. Long-term potentiation (LTP) of CA1 neurons induced by four trains of high-frequency stimulation (HFS) on the Schaffer collaterals was observed in LNA-Scramble group but impaired in LNA-miR132 group. The density of hippocampus synapses was dramatically decreased in LNA-miR132 mice. Inhibition of miR132 result in a significant increased of Methyl CpG binding protein 2[Mecp2] protein, but not mRNA level. These results suggest that miR132-Mecp2 signal passway may be involved in AD-linke learning and memory impairment, but the exactly mechanism is unclear. In the present study, we will Identify the transcripts regulators and target proteins of miR-132. AD-like learning and memory impairment will be attenuates through increase the level of miR-132 transcript regulators or interference the target protein. We want to provide a new molecular mechanism for the impairment of learning and memory result from AD or neurodegenerative diseases and point the way toward a new strategy for treating AD.

miR132富含于小鼠的海马和皮质，并且高表达于神经元。研究表明，miR132在一些伴有学习记忆缺陷的神经退行性疾病中表达显著下调，如阿尔茨海默病、帕金森症等。前期结果显示Tg2576发病小鼠脑组织miR132水平显著低于成年鼠，并且伴随突触相关蛋白PSD95、 NR2B、GluR1的表达下调。特异性抑制小鼠海马miR132后导致小鼠严重的空间和恐惧学习记忆障碍、损伤LTP[长时程增强]的持续性增强和显著降低海马区神经元树突棘密度。以上结果提示miR132下调损伤了海马依赖的学习记忆，但是具体的分子机制还不清楚。本研究拟从分子水平鉴定调控miR132表达的上游关键分子和miR132直接调控的下游靶蛋白，整体动物水平干预上游关键分子和下游靶点蛋白，改善miR132表达下调引起的AD模型鼠的学习记忆障碍。为AD甚至神经退行性疾病导致的学习记忆障碍机制提供新的理论支持，为临床治疗提供新的策略。

miR132富含于小鼠的海马和皮质，并且高表达于神经元。研究表明，miR132在一些伴有学习记忆缺陷的神经退行性疾病中表达显著下调，如阿尔茨海默病、帕金森症等。前期结果显示老龄鼠海马区miR132水平显著低于成年鼠，并且伴随着突触相关蛋白的表达下调。行为学检测显示特异性抑制小鼠海马miR132导致空间和恐惧学习记忆障碍。以上结果提示miR132可能参与了学习记忆的调控，但是具体的分子机制还不清楚。本研究利用AD模型鼠，探讨miR-132/Mecp2信号通路参与AD病理过程的分子机制，并鉴定调控miR-132表达的上游关键分子以及miR-132直接调控的下游靶点蛋白，并通过干扰靶点蛋白的表达水平逆转miR-132下调导致的学习记忆障碍。研究结果显示：① BDNF、CREB可以上调miR-132的表达水平。② Mecp2是miR-132直接作用的下游靶点蛋白。③ miR-132/Mecp2相互作用下调了突触蛋白PSD95，NR2B，GluR1，GluR2，NR1的表达水平。④ miR-132/Mecp2相互作用减少了海马区神经元树突棘的数目以及 LTP表达。⑤ 利用siRNA技术干扰Mecp2的水平能够逆转miR-132下调导致的学习记忆障碍。以上结果证实了miR-132/Mecp2信号通路在AD模型鼠的病理过程中发挥很重要的作用，为理解AD病理过程中的学习记忆障碍机制提供新的理论支持，为临床治疗提供新的策略。