Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature
Lampson M. Fan, … , Keith M. Channon, Jian-Mei Li
Lampson M. Fan, … , Keith M. Channon, Jian-Mei Li
Published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3374-3386. https://doi.org/10.1172/JCI125173.
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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 1

Metabolism and locomotor activities of WT and Nox2KO mice.

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Metabolism and locomotor activities of WT and Nox2KO mice. (A) Metabolic...
(A) Metabolic measurements. SBP, systolic BP. (B) Locomotor horizontal activity measured using motility chambers. Data were collected in 30-minute bins over a 42-hour period. Total activities were calculated and expressed as percent relative to the values of young WT mice (100%). (C) Voluntary running wheel activity measured for 10 days. Average daily activity was calculated and expressed as percent relative to the values of young WT mice (100%). n = 9 mice. *P < 0.05 for indicated values versus young WT value; †P < 0.05 for indicated values versus aging WT values. Statistical analysis was performed using 1-way ANOVA followed by Bonferroni’s post hoc tests.