Activation of the antioxidant regulatory transcription factor NRF2 (Nuclear factor erythroid-derived 2) regulates cellular bioenergetics and improves neuronal health in aging. Yet how NRF2 participates in maintaining synaptic, mitochondrial and cognitive function has not been fully elucidated. This study investigates how loss of NRF2 affects neuronal metabolism, synaptic density and cognitive performance in aged mice. Dendritic arborization as well as synaptic and mitochondrial gene expression was evaluated in hippocampal neurons isolated from mice lacking NRF2 (NRF2KO) and from wild-type (WT) C57BL6 mice. Mitochondrial function of these neurons was evaluated using the Seahorse XF platform. Additionally learning, memory and executive function were assessed in 20 month old NRF2KO and age-matched WT mice using conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) tests. Hippocampal bioenergetics was profiled using mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial and synaptic genes. NRF2KO neurons had reduced dendritic complexity and diminished synaptic gene expression. This was accompanied by impaired mitochondrial function and decreased mitochondrial gene expression. Similar mitochondrial deficits were observed in the brains of aged NRF2KO mice. These animals also had significantly impaired cognitive performance and reduced synaptic gene expression as well. These data point to a role for NRF2 in maintaining mitochondrial and cognitive function during aging and suggest that the transcription factor may be a viable target for cognitive enhancing interventions. Because mitochondrial dysfunction and cognitive impairment also occur together in many neurodegenerative conditions there may be broad therapeutic potential of NRF2 activating agents.

中文翻译：

---

NRF2的丧失导致线粒体功能受损，突触密度降低和与年龄有关的认知缺陷加重。

抗氧化剂调节转录因子NRF2（核因子类胡萝卜素衍生的2）的激活调节细胞生物能，并改善衰老过程中的神经元健康。然而，尚未完全阐明NRF2如何参与维持突触，线粒体和认知功能。这项研究调查了NRF2的损失如何影响老年小鼠的神经元代谢，突触密度和认知能力。在从缺乏NRF2（NRF2KO）的小鼠和野生型（WT）C57BL6小鼠分离的海马神经元中，评估了树突状乔化以及突触和线粒体基因的表达。使用Seahorse XF平台评估了这些神经元的线粒体功能。另外学习 使用条件恐惧反应（CFR）和气味辨别逆向学习（ODRL）测试评估了20个月大的NRF2KO和年龄匹配的WT小鼠的记忆力和执行功能。使用从这些动物中分离的线粒体对海马生物能进行分析，并收集组织用于评估线粒体和突触基因。NRF2KO神经元具有降低的树突状复杂性和减少的突触基因表达。这伴随着线粒体功能受损和线粒体基因表达降低。在老年NRF2KO小鼠的大脑中观察到类似的线粒体缺陷。这些动物的认知能力也明显受损，突触基因表达也降低。这些数据表明NRF2在衰老过程中维持线粒体和认知功能中的作用，并表明转录因子可能是增强认知干预的可行靶标。由于线粒体功能障碍和认知障碍也同时发生在许多神经退行性疾病中，因此NRF2活化剂可能具有广阔的治疗潜力。