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

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

doi:10.1172/jci125173

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.

Highlights

The brain is a highly metabolic organ requiring a consistent supply of oxygen and nutrients for normal function
angiotensin II (Ang II) is a potent activator of endothelial Nox2-NADPH oxidase (Nox2)
This study using age-matched littermates of young (3–4 months) and aging (20–22 months) WT and Nox2KO mice; brain tissues from endothelial cell–specific huNox2Tg mice; and postmortem human midbrain tissues at ages of 25–38 years versus 61–85 years demonstrated that (i) brain oxidative stress attributable to the activation of Nox2-NADPH oxidase plays a key role in aging-related cerebral capillary rarefaction, loss of neurons, and locomotor dysfunction; and (ii) increased endothelial cell ROS production due to endothelial Nox2 overexpression can trigger brain oxidative stress and DNA damage as early as in middle age

Summary

Introduction

The brain is a highly metabolic organ requiring a consistent supply of oxygen and nutrients for normal function. Ensuring a sufficient oxygen and nutrition supply to the brain is accomplished by highly organized cerebral microvascular networks [1]. There is growing evidence that impairment of cerebral microvascular perfusion plays a key role in the development of aging-related neurodegenerative diseases [3]. There is growing interest in life stress and local overproduction of angiotensin II (Ang II) in the brain leading to CNS oxidative stress and cerebral vascular damage [5, 6]. Abnormal upregulation of brain Ang II activity has been observed in animal models of aging, menopause, and chronic cerebral hypoperfusion [5,6,7]. Ang II is a potent activator of endothelial Nox2-NADPH oxidase (Nox2)

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