1.西南医科大学基础医学院,泸州 646000;2.中国科学院生物大分子研究中心,生物大分子国家重点实验室,中国科学院生物物理研究所,北京 100101;3.中国科学院大学,北京 100049;4.北京脑科学与类脑研究中心,北京 102206
国家重点研究研发项目(2017YFA0504000)和国家自然科学基金(31570857,91849203,31800969)资助项目.
1.School of Basic Medical Sciences of Southwest Medical University, Luzhou 646000, China;2.National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;3.University of Chinese Academy of Sciences, Beijing 100049, China;4.National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;5.Chinese Institute for Brain Research, Beijing 102206, China
This work was supported by grants from The National Key Research and Development Program of China (2017YFA0504000) and The National Natural Science Foundation of China (31570857,91849203,31800969).
随着世界人口的老龄化,与年龄相关认知功能障碍的威胁越来越大.研究年龄相关认知功能损伤的发病机制及寻找有效的防治策略具有重要意义.我们之前的研究表明,衰老小鼠海马中S-亚硝基谷胱甘肽还原酶(S-nitrosoglutathione reductase,GSNOR)显著升高,神经元特异性高表达GSNOR转基因小鼠在行为学检测中表现出认知功能障碍.然而,其分子机制仍不清楚.在本研究中发现,CREB信号通路在GSNOR高表达转基因小鼠及原代培养小鼠海马神经元中均被GSNOR下调.在Y迷宫中检测表明,连续7 d腹腔注射CREB激活剂川陈皮素,能改善GSNOR过表达小鼠的认知损伤.进一步通过恐惧箱实验及Y迷宫测试研究川陈皮素对自然衰老小鼠认知功能的作用,发现川陈皮素能显著提高自然衰老小鼠在Y迷宫测试中的正确选择率以及在恐惧箱中的冻结时间,表明川陈皮素能显著改善衰老相关的认知功能.同样,川陈皮素上调了CREB磷酸化以及PSD95和GluR1的水平,表明CREB信号上调在改善自然衰老认知功能损伤中发挥了重要作用.本研究为衰老认知功能损伤机制及改善方法提供了新的依据,GSNOR转基因小鼠也可能成为一种新的认知功能损伤模型.
With the aging of the world's population, the threat of age-related cognitive impairment is increasing. It is of great significance to study the mechanism of age-related cognitive impairment and find effective strategies to rescue it. Our previous studies have demonstrated that S-nitrosoglutathione reductase(GSNOR) was significantly increased in the hippocampus of aging mice and neuronal-specific GSNOR transgenic mice showed cognitive impairment in behavior tests. However, the mechanisms underlying this process remain unclear. Here, we found that CREB signaling was significantly decreased by GSNOR in cultured mice hippocampus neurons and GSNOR transgenic mice. Up regulation of the CREB signaling pathway by nobiletin rescued the cognitive impairment in GSNOR transgenic mice in Y-maze test. Nobiletin also showed protective effects on memory impairment in aging mice model. These results provide a new mechanism for the cognitive impairment in GSNOR transgenic mice and provide a new potential strategy to improve the cognitive function by nobiletin. GSNOR transgenic mice may be used as a screen model as age-related cognitive impairment.
姚勤,张玉英,吴凯源,褚博煜,陈畅.川陈皮素改善衰老认知功能损伤的作用与机制[J].生物化学与生物物理进展,2019,46(6):578-586
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