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  3. 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

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

  • bioRxiv. 2023 Feb 15:2023.02.15.528710. doi: 10.1101/2023.02.15.528710.
Nancy E Ruiz-Uribe,  Oliver Bracko,  Madisen Swallow,  Argen Omurzakov,  Sabyasachi Dash,  Hiroki Uchida,  David Xiang,  Mohammad Haft-Javaherian,  Kaja Falkenhain,  Michael E Lamont,  Muhammad Ali,  Brendah N Njiru,  Hsin-Yun Chang,  Adrian Y Tan,  Jenny Z Xiang,  Costantino Iadecola,  Laibaik Park,  Teresa Sanchez,  Nozomi Nishimura,  Chris B Schaffer
PMID: 36824768 DOI: 10.1101/2023.02.15.528710
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.

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