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

Lampson M Fan1, Li Geng2,3, Sarah Cahill-Smith3

  • 1Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.

The Journal of Clinical Investigation
|July 23, 2019
PubMed

Insights

Nox2 activation contributes to brain aging by increasing reactive oxygen species (ROS), leading to capillary and neuron loss. Reducing Nox2 activity may mitigate age-related cognitive decline and neurodegeneration.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Aging Research

Background:

  • Oxidative stress is a key factor in neurodegeneration associated with aging.
  • The role of Nox2-derived reactive oxygen species (ROS) in brain aging requires further investigation.

Purpose of the Study:

  • To investigate the role of Nox2-derived ROS in age-related neurodegeneration using mouse models.
  • To explore the mechanism of Nox2 activation in endothelial cells and its clinical significance in human aging.

Main Methods:

  • Utilized wild-type (WT), Nox2-knockout (Nox2KO), and human Nox2 transgenic (HuNox2Tg) mice.
  • Examined brain tissues for metabolic disorders, locomotor activity, ROS production, signaling pathway activation (ERK1/2, p53, γH2AX), and capillary/neuronal loss.
  • Investigated Angiotensin II (Ang II)-induced endothelial Nox2 activation in vitro and analyzed postmortem human brain tissues.

Main Results:

  • Aging WT mice exhibited metabolic dysfunction, reduced activity, increased Ang II, ROS, pathway activation, and loss of capillaries/neurons.
  • Nox2KO mice showed significantly reduced abnormalities compared to aging WT mice.
  • HuNox2Tg mice displayed age-like brain changes by middle age, indicating Nox2's role.
  • Endothelial cell studies and human tissue analysis supported Nox2's involvement in capillary damage and aging.

Conclusions:

  • Nox2 activation is a significant contributor to aging-related cerebral capillary rarefaction and neuronal loss.
  • Endothelial cells play a crucial role in Nox2-mediated brain aging processes.
  • Targeting Nox2-derived ROS may offer therapeutic strategies for age-related cognitive decline.
Keywords:
AgingApoptosisNeurodegenerationNeuroscienceendothelial cells

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