Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period.
Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period.
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降低的NRF2表达介导了关键的中年期间神经干细胞功能的下降。
DOI：
10.1111/acel.12482
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发表时间：
2016-08
期刊：
影响因子：
7.8
通讯作者：
Madhavan L
中科院分区：
文献类型：
--
作者：
Corenblum MJ;Ray S;Remley QW;Long M;Harder B;Zhang DD;Barnes CA;Madhavan L
虽然已知神经干/祖细胞（NSPCs）的再生功能随着年龄的增长而下降，但这一现象背后的因果机制尚不清楚。在这里，我们系统地分析了室管膜下区（SVZ）NSPCs，在不同年龄组的大鼠，在体外和体内的组织学和行为学技术。这些研究表明，尽管NSPC功能随着年龄的增长而不断下降，但在中年（13-15个月）期间存在一个关键时期，此时NSPC存活和再生（增殖和神经元分化）发生显著减少。研究还表明，这种特定的NSPC恶化时间模式在行为水平上与功能相关，并与NSPCs中氧化还原敏感性转录因子Nrf 2的表达降低相关。当使用短干扰RNA抑制“年轻”NSPCs中的Nrf 2表达时，NSPCs的存活和再生显著受损，并反映“老”NSPCs。相反，Nrf 2在“老”NSPCs中的过表达使它们与“年轻”NSPCs相似，并且它们显示出增加的存活和再生。此外，对新生Nrf 2敲除（Nrf 2 −/−）小鼠的检查显示，与野生型对照相比，这些动物中的SVZ NSPC数量较低。此外，在Nrf 2 −/−小鼠中，NSPCs的增殖和神经原性潜力也受到损害。这些结果确定了Nrf 2在衰老过程中对NSPC功能的一种新的调节作用，并对开发基于NSPC的策略以支持健康衰老和治疗年龄相关的神经退行性疾病具有重要意义。
Although it is known that the regenerative function of neural stem/progenitor cells (NSPCs) declines with age, causal mechanisms underlying this phenomenon are not understood. Here, we systematically analyze subventricular zone (SVZ) NSPCs, in various groups of rats across the aging spectrum, using in vitro and in vivo histological and behavioral techniques. These studies indicate that although NSPC function continuously declines with advancing age, there is a critical time period during middle age (13–15 months) when a striking reduction in NSPC survival and regeneration (proliferation and neuronal differentiation) occurs. The studies also indicate that this specific temporal pattern of NSPC deterioration is functionally relevant at a behavioral level and correlates with the decreasing expression of the redox‐sensitive transcription factor, Nrf2, in the NSPCs. When Nrf2 expression was suppressed in ‘young’ NSPCs, using short interfering RNAs, the survival and regeneration of the NSPCs was significantly compromised and mirrored ‘old’ NSPCs. Conversely, Nrf2 overexpression in ‘old’ NSPCs rendered them similar to ‘young’ NSPCs, and they showed increased survival and regeneration. Furthermore, examination of newborn Nrf2 knockout (Nrf2 −/−) mice revealed a lower number of SVZ NSPCs in these animals, when compared to wild‐type controls. In addition, the proliferative and neurogenic potential of the NSPCs was also compromised in the Nrf2−/− mice. These results identify a novel regulatory role for Nrf2 in NSPC function during aging and have important implications for developing NSPC‐based strategies to support healthy aging and to treat age‐related neurodegenerative disorders.