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Nox2 contributes to age-related oxidative damage to neurons and the cerebral vasculature.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Jul 22; Vol. 129 (8), pp. 3374-3386. Date of Electronic Publication: 2019 Jul 22 (Print Publication: 2019). - Publication Year :
- 2019
-
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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Aging genetics
Aging pathology
Animals
Capillaries pathology
Endothelium, Vascular pathology
Female
Humans
Male
Mice
Mice, Knockout
Middle Aged
NADPH Oxidase 2 genetics
Neurons
Oxidation-Reduction
Aging metabolism
Brain blood supply
Brain enzymology
Brain pathology
Capillaries enzymology
Endothelial Cells enzymology
Endothelial Cells pathology
Endothelium, Vascular enzymology
NADPH Oxidase 2 metabolism
Reactive Oxygen Species metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 31329158
- Full Text :
- https://doi.org/10.1172/JCI125173