过表达NRF1减轻阿尔茨海默病模型小鼠的线粒体和认知功能障碍
Overexpression of NRF1 alleviates mitochondrial and cognitive dysfunction in mice models of Alzheimer's disease
苏立宁 1王艳兵 2张永财1
作者信息
- 1. 河北北方学院基础医学院,张家口 075000
- 2. 河北北方学院体育部,张家口 075000
- 折叠
摘要
目的 探讨核呼吸因子1(NRF1)对阿尔茨海默病疾病(AD)模型小鼠线粒体及和认知功能障碍的影响.方法 以5×FAD小鼠作为AD模型小鼠,并用脑立体定位注射稀疏标记的过表达NRF1的AAV病毒(AAV-NRF1).,Western blot法测定海马中NRF1的表达;用透射电镜观察海马中线粒体形态;用激光共聚焦显微镜观察CA1区稀疏标记神经元的树突棘并计数;Morris水迷宫实验评估小鼠认知和记忆功能;电生理法检测突触效能的长时程增强效应(LTP).结果 脑立体注射AAV-NRF1后,海马中NRF1表达升高(P＜0.001),海马神经元中线粒体形态明显改善,小鼠的认知和记忆功能提高(P＜0.01),海马CA1区神经元的树突棘密度增加(P＜0.001)并产生持久稳定的LTP且fEPSP斜率增高(P＜0.01).结论 在5 ×FAD小鼠AD模型中,NRF1过表达触发了线粒体功能障碍的修复,并改善了突触可塑性,推测这些改变参与到了过表达NRF1对AD认知功能障碍改善的治疗效果中.
Abstract
Objective To investigate the effects of nuclear respiratory factor 1(NRF1)on mitochondrial and cog-nitive dysfunction in Alzheimer's disease(AD)model mice.Methods The 5 × FAD mice were utilized as a mod-el for Alzheimer's disease,and the sparsely labeled AAV virus overexpressing NRF1(AAV-NRF1)was adminis-tered via stereotaxic injection into the brain.The expression of NRF1 in hippocampus was determined by Western blot,the morphology of mitochondria in hippocampus was observed by transmission electron microscope,the den-dritic spines of sparsely labeled neurons in the CA1 region were visualized and quantified using confocal laser mi-croscopy,cognitive and memory functions of mice were evaluated using the Morris water maze test,while electro-physiological methods were employed to detect long-term potentiation(LTP)of synaptic efficacy.Results The ex-pression of NRF1 in the hippocampus was significantly upregulated following stereotactic injection of AAV-NRF1(P＜0.001).This intervention led to notable improvements in mitochondrial morphology within hippocampal neurons,as well as enhanced cognitive and memory functions in mice(P＜0.01).Moreover,there was a significant in-crease in dendritic spine density among neurons located in the CA1 region of the hippocampus(P＜0.001),ac-companied by long-lasting and stable long-term potentiation(LTP)and a substantial elevation in fEPSP slope(P＜0.01).Conclusion The overexpression of NRF1 in a 5 × FAD mouse model of Alzheimer's disease(AD)initia-ted the restoration of mitochondrial dysfunction and enhanced synaptic plasticity,indicating that these alterations may contribute to the therapeutic efficacy of NRF1 overexpression in ameliorating cognitive dysfunction associated with AD.
关键词
阿尔茨海默病/海马/核呼吸因子1/线粒体/认知功能/基因治疗Key words
Alzheimer's disease/hippocampus/nuclear respiratory factor 1/mitochondria/cognitive function/gene therapy引用本文复制引用
基金项目
河北省年度医学科学研究计划(20200196)
河北北方学院省属高校基本科研项目(JYT2023002)
河北北方学院校级科研项目(H2022405030)
出版年
2024
国家科技期刊平台
NSTL
万方数据