Biology subjects

Ruiz-Uribe, N. E.

Publications and source records attributed to Ruiz-Uribe, N. E..

5 recordsLinked to original sources

bioRxiv2026

Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer's Disease Models

Vascular dysfunction is an increasingly recognized feature of Alzheimer's disease, and inadequate oxygen delivery may contribute to neuronal death. However, how cerebral oxygenation relates to neuronal pathology remains unclear. Here, we used two-photon phosphorescence lifetime microscopy with Oxyphor2P to measure intravascular and tissue partial pressure of oxygen (pO2) at 0, 100 and 200 um cortical depth in awake rTg4510 and THY-Tau22 mice. Relative to WT, capillary and venular pO2 in rTg4510 mice were elevated at 6 months but reduced at 9 months, mainly in deeper layers, with increased oxygen extraction fraction. Suppressing the tau transgene with doxycycline for three months did not restore vascular pO2. THY-Tau22 mice, despite limited tangle pathology, showed even greater reductions in capillary pO2 at every depth. In 6-month-old rTg4510 mice, tissue pO2 trended lower than in WT, and the fraction of low pO2 values (< 18 mmHg) increased with depth, reaching 33% at 200 um versus 4% in WT. Labeling neurofibrillary tangles with the tau-binding dye HS84 revealed significantly lower tissue pO2 in tangle-positive areas at 100 and 200 um. Longitudinal imaging of 2,282 neurons showed that disappearing neurons were not located in relatively hypoxic tissue within an animal. Finally, ex vivo immunostaining revealed neuronal loss and increased astrogliosis in rTg4510 mice, with unchanged vascular architecture. These results indicate that tau disrupts cerebrovascular and tissue oxygenation in a depth- and age-dependent manner, and that neuronal loss is not explained by a neuron's local oxygen microenvironment but may reflect a global reduction in cortical oxygenation.

neuroscience↗

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↗

bioRxiv2020

Voluntary running does not increase capillary blood flow but promotes neurogenesis and short-term memory in the APP/PS1 mouse model of Alzheimers disease

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we examined the impact of three months of voluntary wheel running in [~]1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and cerebral blood flow. Our findings that exercise led to improved memory function, a trend toward reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and no changes in amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall cortical blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer s disease. Overall, our results replicate previous findings that exercise is able to ameliorate certain aspects of Alzheimer s disease pathology, but show that this benefit does not appear to act through increases in cerebral blood flow.

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↗