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Effects of Docosahexaenoic Acid and Its Peroxidation Product on Amyloid-β Peptide-Stimulated Microglia

  • Xue Geng
  • Bo Yang
  • Runting Li
  • Tao Teng
  • Mary Jo Ladu
  • Grace Y. Sun
  • C. Michael Greenlief
  • James C. LeeEmail author
Original Article

Abstract

Growing evidence suggests that docosahexaenoic acid (DHA) exerts neuroprotective effects, although the mechanism(s) underlying these beneficial effects are not fully understood. Here we demonstrate that DHA, but not arachidonic acid (ARA), suppressed oligomeric amyloid-β peptide (oAβ)–induced reactive oxygen species (ROS) production in primary mouse microglia and immortalized mouse microglia (BV2). Similarly, DHA but not ARA suppressed oAβ-induced increases in phosphorylated cytosolic phospholipase A2 (p-cPLA2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) in BV2 cells. LC-MS/MS assay indicated the ability for DHA to cause an increase in 4-hydroxyhexenal (4-HHE) and suppress oAβ-induced increase in 4-hydroxynonenal (4-HNE). Although oAβ did not alter the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, exogenous DHA, ARA as well as low concentrations of 4-HHE and 4-HNE upregulated this pathway and increased production of heme oxygenase-1 (HO-1) in microglial cells. These results suggest that DHA modulates ARA metabolism in oAβ-stimulated microglia through suppressing oxidative and inflammatory pathways and upregulating the antioxidative stress pathway involving Nrf2/HO-1. Understanding the mechanism(s) underlying the beneficial effects of DHA on microglia should shed light into nutraceutical therapy for the prevention and treatment of Alzheimer’s disease (AD).

Keywords

Alzheimer’s disease Fish oil Omega-3 fatty acids Phospholipase A2 Lipid peroxidation 

Notes

Acknowledgments

We thank Dr. Brian Mooney, associate director of the Charles W. Gehrke Proteomics Center at the University of Missouri, for providing assistance with the LC-MS/MS.

Funding Information

This study is supported by a National Institutes of Health grant R01-AG044404 (to J. C. L.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Richard and Loan Hill Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of ChemistryUniversity of MissouriColumbiaUSA
  3. 3.Department of BiochemistryUniversity of MissouriColumbiaUSA
  4. 4.Department of Anatomy and Cell BiologyUniversity of Illinois at ChicagoChicagoUSA
  5. 5.UIC Bioengineering (MC 063)ChicagoUSA

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