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

Ruiz-Uribe, N. E.; Bracko, O.; Swallow, M.; Omurzakov, A.; Dash, S.; Uchida, H.; Xiang, D.; Haft-Javaherian, M.; Falkenhain, K.; Lamont, M. E.; Ali, M.; Njiru, B. N.; Chang, H.-Y.; Tan, A. Y.; Xiang, J. Z.; Iadecola, C.; Park, L.; Sanchez, T.; Nishimura, N.; Schaffer, C. B.

doi:10.1101/2023.02.15.528710

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bioRxiv · 10.1101/2023.02.15.528710

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

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Abstract

INTRODUCTIONIn 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. METHODSWe 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. RESULTSWe 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. DISCUSSIONOxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

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Ruiz-Uribe, N. E., Bracko, O., Swallow, M., Omurzakov, A., Dash, S., Uchida, H., Xiang, D., Haft-Javaherian, M., Falkenhain, K., Lamont, M. E., Ali, M., Njiru, B. N., Chang, H.-Y., Tan, A. Y., Xiang, J. Z., Iadecola, C., Park, L., Sanchez, T., Nishimura, N., Schaffer, C. B.. 2023-02-15. 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. https://doi.org/10.1101/2023.02.15.528710

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