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Neutrophil adhesion in brain capillaries contributes to cerebral blood flow deficits in APP/PS1 mice and is dependent on oxidative stress pathways
Author(s) -
RuizUribe Nancy E.,
Bracko Oliver,
Swallow Madison,
Ali Muhammad,
Njiru Brendah N.,
Falkenhain Kaja,
Chang HsinYun,
Iadecola Costantino,
Park Laibaik,
Nishimura Nozomi,
Schaffer Chris B.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043267
Subject(s) - oxidative stress , inflammation , cerebral blood flow , endothelium , blood–brain barrier , nadph oxidase , microbiology and biotechnology , reactive oxygen species , chemistry , amyloid precursor protein , endothelial dysfunction , endothelial activation , alzheimer's disease , immunology , biology , endocrinology , medicine , central nervous system , disease
Background Cerebral blood flow (CBF) is decreased by ∼30% in both human patients and animal models of Alzheimer’s disease (AD). Previously, we found that about 2% of cortical capillaries in the APP/PS1 mouse model of AD had stalled blood flow due to an adhered neutrophil, while only 0.4% of capillaries were stalled in wild type controls. Blocking neutrophil adhesion in the APP/PS1 mice released the adhered cells, leading to increased CBF and improved cognitive function. Here, we report on the upstream molecular mechanisms contributing to the increased neutrophil adhesion, focusing on oxidative stress pathways that have previously been implicated in endothelial dysfunction in AD, including the loss of neurovascular regulation. Method We inhibited NOX2‐containing NAPDH‐oxidase, a reactive oxygen species producing enzyme shown to be activated in AD, in 10‐11 month old APP/PS1 mice for two weeks. Result We found that, in APP/PS1 mice, the fraction of capillaries with stalled blood flow was decreased by 67%, CBF was increased by 29%, and performance on short‐term memory tasks was improved. Enzyme‐linked immunosorbent assays showed no significant changes in amyloid‐beta levels and the overall plaque load was not affected. A decrease in the brain levels of activated astrocytes was detected, suggesting that NOX2 inhibition reduces overall inflammation. Conclusion This study implicates the NOX2 pathway as a molecular mechanism likely underlying the vascular inflammation that contributes to capillary stalling and CBF reductions in a mouse model of AD and could represent a molecular pathway with potential therapeutic targets for AD.