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Abstract
Originally Published 30 January 2025
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Abstract WMP117: SARS-CoV-2 infection worsens neuroinflammation and brain senescence in an endothelial nitric oxide synthase deficient model of vascular dementia.

Abstract

Introduction: SARS-CoV-2 causes various neurological sequelae in COVID-19 survivors including fatigue and cognitive dysfunction. Endothelial dysfunction, a key mechanism in COVID-19 illness, is also a major risk factor for vascular dementia (VaD). Clinical evidence suggests that reduced nitric oxide (NO) bioavailability is a likely pathogenic factor of endothelial dysfunction in COVID-19 patients, and eNOS levels decline with advancing age, a risk factor for both COVID-19 morbidity and VaD . We hypothesize that endothelial nitric oxide synthase (eNOS) deficiency contributes to brain endothelial dysfunction in SARS-CoV-2 infection and that SARS-CoV-2 infection accelerates the onset of VaD in eNOS-deficient mice.
Methods: 6-month-old eNOS+/- (pre-cognitively impaired experimental VaD) and WT male mice were infected with 1X104-pfu mouse-adapted (MA10) SARS-CoV-2 intranasally, and animals were evaluated acutely out to 3-days-postinfection (3dpi) for changes in body weight and clinical signs of illness. Viral copy numbers and nuclear capsid were also quantified in lung and brain. Quantitative PCR and immunofluorescence were used to analyze markers of brain inflammation and senescence.
Results: eNOS+/- infected mice exhibited more disease-associated weight loss (~15%) than WT-infected mice (~5 %). While infected WT and eNOS+/- had comparable pulmonary viral load, neither had detectable virus in the brain. Quantitative PCR analysis of whole brain-isolated mRNA showed increases in multiple proinflammatory mediators such as CCL2 and IL-6 and senescence markers such as p53 and p21 (eNOS+/- >> WT). Similarly, immunofluorescent analysis showed increased Iba1 (microglia marker) fluorescent intensity in the cortex of infected mice (eNOS+/- >> WT).
Conclusions: eNOS+/- deficiency, a clinically relevant model of VaD, worsens acute SARS-CoV-2-associated morbidity, neuroinflammation and markers of brain senescence despite comparable pulmonary viral load (to WT-infected animals) and absence of virus in the brain. While the potential effects of SARS-COV-2 on cognitive decline in this model will be assessed in future studies, this is the first experimental evidence demonstrating a link between eNOS and neuropathology associated with COVID-19.

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Published online: 30 January 2025
Published in print: February 2025

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Keywords

  1. Post-COVID
  2. Vascular cognitive impairment

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Saifudeen Ismael, PhD
Tulane University, New Orleans, Louisiana, United States
Meenakshi Umar, PhD, MSc
Tulane University, New Orleans, Louisiana, United States
Blake Ouvrier, MS, BS
Tulane University, New Orleans, Louisiana, United States
Gregory Bix, MD, PhD
TULANE UNIVERSITY, New Orleans, Louisiana, United States

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For author disclosure information, please visit the AHA International Stroke Conference website.

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Abstract WMP117: SARS-CoV-2 infection worsens neuroinflammation and brain senescence in an endothelial nitric oxide synthase deficient model of vascular dementia.
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