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Lookup NU author(s): Professor Raj KalariaORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2022. Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease.
Author(s): Alfieri A, Koudelka J, Li M, Scheffer S, Duncombe J, Caporali A, Kalaria RN, Smith C, Shah AM, Horsburgh K
Publication type: Article
Publication status: Published
Journal: Journal of Cerebral Blood Flow and Metabolism
Year: 2022
Volume: 42
Issue: 7
Pages: 1176-1191
Print publication date: 01/07/2022
Online publication date: 01/02/2022
Acceptance date: 06/12/2021
Date deposited: 05/03/2024
ISSN (print): 0271-678X
ISSN (electronic): 1559-7016
Publisher: SAGE Publications Ltd
URL: https://doi.org/10.1177/0271678X221077766
DOI: 10.1177/0271678X221077766
PubMed id: 35102790
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