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Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline

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.

Publication metadata

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


DOI: 10.1177/0271678X221077766

PubMed id: 35102790


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Funder referenceFunder name
152 (PG-157)
228 (AS-DTC-2014-017)
ARUK-PG2013-22Alzheimer`s Research UK
290 (AS-PG-15b-018)
British Heart Foundation
Alzheimer's Research UK (ARUK)
Alzheimer's Society
Alzheimer's Society Doctoral Training PhD studentship
RS McDonald Charitable Trust