Wang Chun-Yan, Wang Zhan-You, Xie Jing-Wei, Cai Jian-Hui, Wang Tao, Xu Ye, Wang Xu, An Li
1 Key Laboratory of Medical Cell Biology of Ministry of Education of China, Department of Pathophysiology, China Medical University , Shenyang, China .
Antioxid Redox Signal. 2014 Dec 1;21(16):2208-30. doi: 10.1089/ars.2014.5845. Epub 2014 May 16.
There is extensive evidence that oxidative stress induces cellular dysfunction in the brain and plays a critical role in Alzheimer's disease (AD) pathogenesis. Hypoxia increases factors involved in oxidative stress injury and contributes to the onset and progression of AD. Nuclear factor erythroid 2-related factor 2 (NRF2), a major component regulating antioxidant response, is attenuated in the AD brain. Importantly, NRF2 directly regulates the alternative first exons of CD36, an important participant in oxidative and inflammatory processes. To explore the effects of hypoxia-induced deterioration of AD-like pathogenesis and investigate the correlation between hypoxia-induced NRF2 signal alterations and CD36 expression, we examined the NRF2 signaling, CD36, and oxidative stress events in hypoxia-treated APPswe/PSEN1dE9 (APP/PS1) mice brain.
We observed that hypoxia treatment increased oxidative stress, exacerbated inflammation, and aggravated learning defects in aged APP/PS1 mice. Microglia from hypoxia-treated mice brain exhibited marked reduction in CD36 expression and inhibition of β-amyloid (Aβ) degradation. Accordingly, hypoxia treatment caused a decrease in transactivation of NRF2 target genes in the aging mouse brain. Intranasal administration with a lentiviral vector encoding human NRF2 increased CD36 expression, ameliorated the weak antioxidant response triggered by hypoxia, diminished Aβ deposition, and improved spatial memory defects.
In this study, we demonstrated for the first time that NRF2 intranasal treatment-induced increases of CD36 could enhance Aβ clearance in AD transgenic mouse.
These results suggest that targeting NRF2-mediated CD36 expression might provide a beneficial intervention for cognitive impairment and oxidative stress in AD progression.
有大量证据表明氧化应激会诱发大脑细胞功能障碍，并在阿尔茨海默病（AD）发病机制中起关键作用。缺氧会增加氧化应激损伤相关因子，并促使AD的发生和发展。核因子红细胞2相关因子2（NRF2）是调节抗氧化反应的主要成分，在AD大脑中会减弱。重要的是，NRF2直接调节CD36的可变第一外显子，CD36是氧化和炎症过程中的重要参与者。为了探究缺氧诱导的AD样发病机制恶化的影响，并研究缺氧诱导的NRF2信号改变与CD36表达之间的相关性，我们检测了缺氧处理的APPswe/PSEN1dE9（APP/PS1）小鼠大脑中的NRF2信号、CD36和氧化应激事件。
我们观察到缺氧处理会增加氧化应激、加剧炎症，并加重老年APP/PS1小鼠学习缺陷。缺氧处理小鼠大脑中的小胶质细胞显示CD36表达显著降低，且β淀粉样蛋白（Aβ）降解受到抑制。相应地，缺氧处理导致衰老小鼠大脑中NRF2靶基因的反式激活减少。经鼻内给予编码人NRF2的慢病毒载体可增加CD36表达，改善缺氧引发的弱抗氧化反应，减少Aβ沉积，并改善空间记忆缺陷。
在本研究中，我们首次证明经鼻内给予NRF2可诱导CD36增加，从而增强AD转基因小鼠中的Aβ清除。
这些结果表明，针对NRF2介导的CD36表达进行干预可能为AD进展中的认知障碍和氧化应激提供有益的治疗方法。
