Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature
Lampson M. Fan, Li Geng, Sarah Cahill-Smith, Fangfei Liu, Gillian Douglas, Chris-Anne Mckenzie, Colin Smith, Gavin Brooks, Keith M. Channon, Jian-Mei Li
Lampson M. Fan, Li Geng, Sarah Cahill-Smith, Fangfei Liu, Gillian Douglas, Chris-Anne Mckenzie, Colin Smith, Gavin Brooks, Keith M. Channon, Jian-Mei Li
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Research Article Aging Neuroscience

Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature

Abstract

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 γH2AX; 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.

Authors

Lampson M. Fan, Li Geng, Sarah Cahill-Smith, Fangfei Liu, Gillian Douglas, Chris-Anne Mckenzie, Colin Smith, Gavin Brooks, Keith M. Channon, Jian-Mei Li

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Figure 4

Age-associated increases in ROS production and in levels of Ang II and VCAM-1 expression in midbrain tissues of WT and Nox2KO mice.

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Age-associated increases in ROS production and in levels of Ang II and V...
(A) ROS production detected by lucigenin chemiluminescence. (B) Inhibitor assay. The effects of different enzyme inhibitors on ROS production by aging WT midbrain tissues detected by lucigenin chemiluminescence. #P < 0.05 for indicated values versus aging WT control values without inhibitor. MLU, mean light units. (C) Brain tissue lipid peroxidation detected by MDA assay. (D) Brain tissue O2•– production detected by SOD-inhibitable cytochrome c reduction assay. (E) Brain tissue H2O2 production detected by catalase-inhibitable Amplex red assay. Nox2tat was used to inhibit Nox2. (F) Brain tissue Ang II levels detected by ELISA. (G) Vascular inflammation maker (VCAM-1) expression detected by Western blot analysis. ODs of protein bands were quantified and normalized to α-tubulin detected in the same sample. n = 6 mice/group. *P < 0.05 for indicated values versus young values in the same genetic group; †P < 0.05 for indicated values versus WT values in the same age group (A, C, D, and F) or for indicated values versus values without inhibitor in the same age and genetic group (E). Statistical analysis was performed using 1-way ANOVA followed by Bonferroni’s post hoc tests.