Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature
Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature
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DOI：
10.1172/jci125173
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发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Li, Jian-Mei
中科院分区：
文献类型：
--
作者：
Fan, Lampson M.;Geng, Li;Li, Jian-Mei
氧化应激在衰老相关的神经退行性变中起重要作用。本研究使用WT和Nox 2敲除（Nox 2KO）小鼠加上内皮细胞特异性人Nox 2过表达转基因（HuNox 2 Tg）小鼠的同窝仔来研究Nox 2衍生的ROS在脑老化中的作用。与年轻的WT小鼠（3-4个月）相比，老龄WT小鼠（20-22个月）具有明显的代谢紊乱和运动活动的丧失。衰老的WT脑具有高水平的血管紧张素II（Ang II）和ROS产生; ERK 1/2、p53和γ H2 AX的活化;以及毛细血管和神经元的损失。然而，这些异常在老化的Nox 2KO大脑中显著减少。中年（11-12个月）的HuNox 2 Tg大脑已经具有高水平的ROS产生和应激信号通路的激活，类似于在衰老的WT大脑中发现的那些。血管紧张素II诱导的内皮细胞Nox 2激活毛细血管损伤的机制进行了研究，使用原代脑微血管内皮细胞。使用年轻人（25-38岁）和老年人（61-85岁）的死后中脑组织研究了Nox 2衍生的ROS在脑毛细血管和神经元老化相关损失中的临床意义。总之，Nox 2激活是衰老相关的脑毛细血管稀疏和脑功能降低的重要机制，内皮细胞可能起关键作用。
Oxidative stress plays an important role in aging-related neurodegeneration. This study used littermates of WT and Nox2-knockout (Nox2KO) mice plus endothelial cell-specific human Nox2 overexpression-transgenic (HuNox2Tg) mice to investigate Nox2-derived ROS in brain aging. Compared with young WT mice (3-4 months), aging WT mice (20-22 months) had obvious metabolic disorders and loss of locomotor activity. Aging WT brains had high levels of angiotensin II (Ang II) and ROS production; activation of ERK1/2, p53, and gamma H2AX; and losses of capillaries and neurons. However, these abnormalities were markedly reduced in aging Nox2KO brains. HuNox2Tg brains at middle age (11-12 months) already had high levels of ROS production and activation of stress signaling pathways similar to those found in aging WT brains. The mechanism of Ang II-induced endothelial Nox2 activation in capillary damage was examined using primary brain microvascular endothelial cells. The clinical significance of Nox2-derived ROS in aging-related loss of cerebral capillaries and neurons was investigated using postmortem midbrain tissues of young (25-38 years) and elderly (61-85 years) adults. In conclusion, Nox2 activation is an important mechanism in aging-related cerebral capillary rarefaction and reduced brain function, with the possibility of a key role for endothelial cells.