Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline

• Published in: Journal of cerebral blood flow and metabolism Vol. 42; no. 7; pp. 1176 - 1191
• Main Authors: Alfieri, Alessio, Koudelka, Juraj, Li, Mosi, Scheffer, Sanny, Duncombe, Jessica, Caporali, Andrea, Kalaria, Rajesh N, Smith, Colin, Shah, Ajay M, Horsburgh, Karen
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.07.2022
• Subjects: Animals; Carotid Stenosis; Cognitive Dysfunction - pathology; Inflammation - pathology; Mice; Mice, Inbred C57BL; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; Original; White Matter - pathology; cerebral hypoperfusion; white matter; Vascular cognitive impairment; inflammation; NADPH oxidase
• ISSN: 0271-678X; 1559-7016; 1559-7016
• DOI: 10.1177/0271678X221077766

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.