Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease

Brandy L. Wilkinson, Paige E. Cramer, Nicholas H. Varvel, Erin Reed-Geaghan, Qingguang Jiang, Alison Szabo, Karl Herrup, Bruce T. Lamb, Gary E. Landreth

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Considerable evidence points to important roles for inflammation in Alzheimer's disease (AD) pathophysiology. Epidemiological studies have suggested that long-term nonsteroidal anti-inflammatory drug (NSAID) therapy reduces the risk for Alzheimer's disease; however, the mechanism remains unknown. We report that a 9-month treatment of aged R1.40 mice resulted in 90% decrease in plaque burden and a similar reduction in microglial activation. Ibuprofen treatment reduced levels of lipid peroxidation, tyrosine nitration, and protein oxidation, demonstrating a dramatic effect on oxidative damage in vivo. Fibrillar β-amyloid (Aβ) stimulation has previously been demonstrated to induce the assembly and activation of the microglial nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to superoxide production through a tyrosine kinase-based signaling cascade. Ibuprofen treatment of microglia or monocytes with racemic or S-ibuprofen inhibited Aβ-stimulated Vav tyrosine phosphorylation, NADPH oxidase assembly, and superoxide production. Interestingly, Aβ-stimulated Vav phosphorylation was not inhibited by COX inhibitors. These findings suggest that ibuprofen acts independently of cyclooxygenase COX inhibition to disrupt signaling cascades leading to microglial NADPH oxidase (NOX2) activation, preventing oxidative damage and enhancing plaque clearance in the brain.

Original languageEnglish (US)
Pages (from-to)197.e21-197.e32
JournalNeurobiology of Aging
Volume33
Issue number1
DOIs
StatePublished - Jan 2012

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Keywords

  • Alzheimer's disease
  • Microglia
  • NADPH oxidase
  • NSAIDs
  • Oxidative stress
  • Vav

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Wilkinson, B. L., Cramer, P. E., Varvel, N. H., Reed-Geaghan, E., Jiang, Q., Szabo, A., Herrup, K., Lamb, B. T., & Landreth, G. E. (2012). Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease. Neurobiology of Aging, 33(1), 197.e21-197.e32. https://doi.org/10.1016/j.neurobiolaging.2010.06.014