Biology subjects

Njiru, B. N.

Publications and source records attributed to Njiru, B. N..

4 recordsLinked to original sources

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2021

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimers disease mouse model

Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimers disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.

neuroscience↗

bioRxiv2019

High fat diet worsens pathology and impairment in an Alzheimers mouse model, but not by synergistically decreasing cerebral blood flow

Obesity is linked to increased risk for and severity of Alzheimers disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We showed that non-flowing capillaries, caused by adhered neutrophils, underlie the CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd. Significance statementObesity, especially in mid-life, has been linked to increased risk for and severity of Alzheimers disease. Here, we show that blocking adhesion of white blood cells leads to increases in brain blood flow that improve cognitive function, regardless of whether mice are obese or not.

neuroscience↗

bioRxiv2019

Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice

Alzheimers disease (AD) is associated with a 20-30% reduction in cerebral blood flow. In the APP/PS1 mouse model of AD, inhibiting neutrophil adhesion using an antibody against the neutrophil specific protein Ly6G was recently shown to drive rapid improvements in cerebral blood flow that was accompanied by an improvement in performance on short-term memory tasks. Here, in a longitudinal aging study, we assessed how far into disease development a single injection of anti-Ly6G can acutely improve memory function. We found that APP/PS1 mice as old as 15-16 months had improved performance on the object replacement and Y-maze tests of short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice 17-18 months of age or older did not show acute improvements in cognitive performance, although we did find that cerebral blood flow was still increased by 17% in 21-22 months old APP/PS1 mice given anti-Ly6G. These data add to the growing body of evidence suggesting that cerebral blood flow reductions are an important contributing factor to the cognitive dysfunction associated with neurodegenerative disease.

neuroscience↗