Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer’s disease.

TitleVascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer’s disease.
Publication TypeJournal Article
Year of Publication2023
AuthorsRuiz-Uribe NE, Bracko O, Swallow M, Omurzakov A, Dash S, Uchida H, Xiang D, Haft-Javaherian M, Falkenhain K, Lamont ME, Ali M, Njiru BN, Chang H-Y, Tan AY, Xiang JZ, Iadecola C, Park L, Sanchez T, Nishimura N, Schaffer CB
JournalbioRxiv
Date Published2023 Feb 15
Abstract

INTRODUCTION: In this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD.

METHODS: We inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels.

RESULTS: We found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways.

DISCUSSION: Oxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

DOI10.1101/2023.02.15.528710
Alternate JournalbioRxiv
PubMed ID36824768
PubMed Central IDPMC9949082