Skip to main content

Omega-3 Essential Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease


The significance of the selective enrichment in omega-3 essential fatty acids in photoreceptors and synaptic membranes of the nervous system has remained, until recently, incompletely understood. While studying mechanisms of cell survival in neural degeneration, we discovered a docosanoid synthesized from unesterified docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). This lipid mediator is a docosanoid because it is derived from the 22 carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20 carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We discovered that NPD1 is promptly made in response to oxidative stress, as a response to brain ischemia–reperfusion, and in the presence of neurotrophins. NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed retinal pigment epithelial (RPE) cells, and in human brain cells exposed to amyloid-β (Aβ) peptides. We thus envision NPD1 as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by imbalances in normal neural function. We provide here, in three sections, recent experimental examples that highlight the specificity and potency of NPD1 spanning beneficial bioactivity during initiation and early progression of neurodegeneration: (1) during retinal signal phototransduction, (2) during brain ischemia–reperfusion, and (3) in Alzheimer's disease (AD) and stressed human brain cell models of AD. From this experimental evidence, we conclude that DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.

This is a preview of subscription content, access via your institution.

Fig. 1



amyloid beta 42 amino acid peptide


arachidonic acid


a disintegrin and metalloprotease


Alzheimer's disease


α-linolenic acid


apolipoprotein E4 allele


β-amyloid cleavage enzyme


beta-amyloid precursor protein


inducible cyclooxygenase-2

cPLA2 :

cytosolic phospholipase A2


docosahexaenoic acid


eicosapentanoic acid


hydroxyeicosatetraenoic acids










neurofibrillary tangles


neuroprotectin D1


neurovascular unit



PLA2 :

phospholipase A2


photoreceptor outer segment


polyunsaturated fatty acid


reactive oxygen species


retinal pigment epithelial


senile plaque


soluble amyloid precursor protein alpha fragment


tumor necrosis factor alpha inducible protein-2 (B94)


  1. Abete P, Testa G, Galizia G, Della-Morte D, Cacciatore F, Rengo F (2009) PUFA for human health: diet or supplementation? Curr Pharm Des 15:4186–4190

    Article  CAS  PubMed  Google Scholar 

  2. Cole GM, Frautschy SA (2010) DHA may prevent age-related dementia. J Nutr 140(4):869–874

    Article  PubMed  CAS  Google Scholar 

  3. Marszalek JR, Lodish HF (2005) Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function. Annu Rev Cell Dev Biol 21:633–657

    Article  CAS  PubMed  Google Scholar 

  4. Singh M (2005) Essential fatty acids, DHA and the human brain. Indian J Pediatr 72:239–242

    Article  PubMed  Google Scholar 

  5. Rapoport SI, Rao JS, Igarashi M (2007) Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot Essent Fat Acids 77:251–261

    Article  CAS  Google Scholar 

  6. Innis SM (2007) Dietary (n-3) fatty acids and brain development. J Nutr 137:855–859

    CAS  PubMed  Google Scholar 

  7. Spector AA (2001) Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. J Mol Neurosci 16:159–165

    Article  CAS  PubMed  Google Scholar 

  8. Scott BL, Bazan NG (1989) Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc Natl Acad Sci 86:2903–2907

    Article  CAS  PubMed  Google Scholar 

  9. Lukiw WJ, Cui JG, Marcheselli VL, Boedker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 115:2774–2783

    Article  CAS  PubMed  Google Scholar 

  10. Zhang C, Bazan NG (2010) Lipid-mediated cell signaling protects against injury and neurodegeneration. J Nutr. Feb 24

  11. Bazan NG (2009) Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection. Prostaglandins Leukot Essent Fat Acids 81:205–211

    Article  CAS  Google Scholar 

  12. Bazan NG (2009) Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease. J Lipid Res 50:400–405

    Article  CAS  Google Scholar 

  13. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG (2003) Novel docosanoids inhibit brain ischemia–reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278:43807–43817

    Article  CAS  PubMed  Google Scholar 

  14. Calon F, Cole G (2007) Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot Essent Fat Acids 77:287–293

    Article  CAS  Google Scholar 

  15. Muldoon MF, Ryan CM, Sheu L, Yao JK, Conklin SM, Manuck SB (2010) Serum phospholipid docosahexaenonic acid is associated with cognitive functioning during middle adulthood. J Nutr 140(4):848–853

    Article  PubMed  CAS  Google Scholar 

  16. Johnson EJ, McDonald K, Caldarella SM, Chung HY, Troen AM, Snodderly DM (2008) Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr Neurosci 11:75–83

    Article  CAS  PubMed  Google Scholar 

  17. DHA-EPA Omega-3 Institute (2010)

  18. Mukherjee PK, Chawla A, Loayza MS, Bazan NG (2007) Docosanoids are multifunctional regulators of neural cell integrity and fate: significance in aging and disease. Prostaglandins Leukot Essent Fat Acids 77:233–238

    Article  CAS  Google Scholar 

  19. Rodriguez de Turco EB, Parkins N, Ershov AV, Bazan NG (1999) Selective retinal pigment epithelial cell lipid metabolism and remodeling conserves photoreceptor docosahexaenoic acid following phagocytosis. J Neurosci Res 57:479–486

    Article  CAS  PubMed  Google Scholar 

  20. Mukherjee PK, Marcheselli VL, de Rivero Vaccari JC, Gordon WC, Jackson FE, Bazan NG (2007) Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis. Proc Natl Acad Sci 104:13158–13163

    Article  CAS  PubMed  Google Scholar 

  21. Hayashi H, Yamashiro K, Tsujikawa A, Ota M, Otani A, Yoshimura N (2009) Association between foveal photoreceptor integrity and visual outcome in neovascular age-related macular degeneration. Am J Ophthalmol 148:83–91

    Article  PubMed  Google Scholar 

  22. Bazan NG (2007) Homeostatic regulation of photoreceptor cell integrity: significance of the potent mediator neuroprotectin D1 biosynthesized from docosahexaenoic acid: the Proctor Lecture. Invest Ophthalmol Vis Sci 48:4866–4881

    Article  PubMed  Google Scholar 

  23. Chiu CJ, Klein R, Milton RC, Gensler G, Taylor A (2009) Does eating particular diets alter the risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? Br J Ophthalmol 93:1241–1246

    Article  PubMed  Google Scholar 

  24. Cakiner-Egilmez T (2008) Omega 3 fatty acids and the eye. Insight 33:20–25

    PubMed  Google Scholar 

  25. McGahon BM, Martin DS, Horrobin DF, Lynch MA (1999) Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids. Neuroscience 94:305–314

    Article  CAS  PubMed  Google Scholar 

  26. Johnson EJ (2010) Age-related macular degeneration and antioxidant vitamins: recent findings. Curr Opin Clin Nutr Metab Care 13:28–33

    Article  PubMed  Google Scholar 

  27. Li F, Marchette LD, Brush RS, Elliott MH, Le YZ, Henry KA, Anderson AG, Zhao C, Sun X, Zhang K, Anderson RE (2009) DHA does not protect ELOVL4 transgenic mice from retinal degeneration. Mol Vis 15:1185–1193

    CAS  PubMed  Google Scholar 

  28. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738

    CAS  PubMed  Google Scholar 

  29. Eddy DE, Harman D (1977) Free radical theory of aging: effect of age, sex and dietary precursors on rat-brain docosahexanoic acid. J Am Geriatr Soc 25:220–229

    CAS  PubMed  Google Scholar 

  30. Charnock JS, McLennan PL, Abeywardena MY (1992) Dietary modulation of lipid metabolism and mechanical performance of the heart. Mol Cell Biochem 116:19–25

    Article  CAS  PubMed  Google Scholar 

  31. Mano MT, Bexis S, Abeywardena MY, McMurchie EJ, King RA, Smith RM, Head RJ (1995) Fish oils modulate blood pressure and vascular contractility in the rat and vascular contractility in the primate. Blood Press 4:177–186

    Article  CAS  PubMed  Google Scholar 

  32. Glozman S, Green P, Yavin E (1998) Intraamniotic ethyl docosahexaenoate administration protects fetal rat brain from ischemic stress. J Neurochem 70:2484–2491

    CAS  PubMed  Article  Google Scholar 

  33. Miyauchi O, Mizota A, Adachi-Usami E, Nishikawa M (2001) Protective effect of docosahexaenoic acid against retinal ischemic injury: an electroretinographic study. Ophthalmic Res 33:191–195

    Article  CAS  PubMed  Google Scholar 

  34. Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH (2005) Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg 18:335–350

    Article  PubMed  Google Scholar 

  35. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and the blood–brain barrier disorder in Alzheimer's disease. Acta Neuropathol 118:103–113

    Article  CAS  PubMed  Google Scholar 

  36. Bazan NG, Marcheselli VL, Cole-Edwards K (2005) Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. Ann N Y Acad Sci 1053:137–147

    Article  CAS  PubMed  Google Scholar 

  37. Niemoller TD, Bazan NG (2009) Docosahexaenoic acid neurolipidomics. Prostaglandins Other Lipid Mediat 91(3–4):85–89

    PubMed  Google Scholar 

  38. Belayev L, Khoutorova L, Atkins KD, Bazan NG (2009) Robust docosahexaenoic acid-mediated neuroprotection in a rat model of transient, focal cerebral ischemia. Stroke 40:3121–3126

    Article  CAS  PubMed  Google Scholar 

  39. Mancuso M, Coppede F, Migliore L, Siciliano G, Murri L (2006) Mitochondrial dysfunction, oxidative stress and neurodegeneration. J Alzheimers Dis 10:59–73

    CAS  PubMed  Google Scholar 

  40. Kazantsev AG (2007) Cellular pathways leading to neuronal dysfunction and degeneration. Drug News Perspect 20:501–509

    Article  CAS  PubMed  Google Scholar 

  41. Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer's disease amyloid beta peptide. Biochim Biophys Acta 1768:1976–1990

    Article  CAS  PubMed  Google Scholar 

  42. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70:462–473

    Article  CAS  PubMed  Google Scholar 

  43. Lukiw WJ (2004) Gene expression profiling in fetal, aged and Alzheimer hippocampus—a continuum of stress-related signaling. Neurochem Res 29:1287–1297

    Article  CAS  PubMed  Google Scholar 

  44. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362:329–344

    Article  CAS  PubMed  Google Scholar 

  45. Tabaton M, Zhu X, Perry G, Smith MA, Giliberto L (2010) Signaling effect of amyloid-beta(42) on the processing of AbetaPP. Exp Neurol 221:18–25

    Article  CAS  PubMed  Google Scholar 

  46. McNaull BB, Todd S, McGuinness B, Passmore AP (2010) Inflammation and anti-inflammatory strategies for Alzheimer's disease. Gerontology 56:3–14

    Article  CAS  PubMed  Google Scholar 

  47. Lukiw WJ (2009) Docosahexaenoic acid and amyloid-beta peptide signaling in Alzheimer's disease. World Rev Nutr Diet 99:55–70

    Article  CAS  PubMed  Google Scholar 

  48. Rabinovici GD, Jagust WJ (2009) Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behav Neurol 21:117–128

    CAS  PubMed  Google Scholar 

  49. Hensley K (2010) Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis. Feb 24 (in press)

  50. Randall AD, Witton J, Booth C, Hynes-Allen A, Brown JT (2010) The functional neurophysiology of the amyloid precursor protein (APP) processing pathway. Neuropharmacology. Feb 16 (in press)

  51. Sultana R, Butterfield DA (2010) Role of oxidative stress in the progression of Alzheimer's disease. J Alzheimers Dis 19:341–353

    PubMed  Google Scholar 

  52. Butterfield DA, Lange ML, Sultana R (2010) Involvements of the lipid peroxidation product, HNE, in the pathogenesis and progression of Alzheimer's disease. Biochim Biophys Acta. Feb 19 (in press)

  53. Martín V, Fabelo N, Santpere G, Puig B, Marín R, Ferrer I, Díaz M (2010) Lipid alterations in lipid rafts from Alzheimer's disease human brain cortex. J Alzheimers Dis 19:489–502

    PubMed  Google Scholar 

  54. Lukiw WJ, Bazan NG (2006) Survival signaling in Alzheimer's disease. Biochem Soc Trans 34:1277–1282

    Article  CAS  PubMed  Google Scholar 

  55. Kim YJ, Chung HY (2007) Antioxidative and anti-inflammatory actions of docosahexaenoic acid and eicosapentaenoic acid in renal epithelial cells and macrophages. J Med Food 10:225–231

    Article  CAS  PubMed  Google Scholar 

  56. Montine TJ, Morrow JD (2005) Fatty acid oxidation in the pathogenesis of Alzheimer's disease. Am J Pathol 166:1283–1289

    CAS  PubMed  Google Scholar 

  57. Cole GM, Ma QL, Frautschy SA (2009) Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fat Acids 81:213–221

    Article  CAS  Google Scholar 

  58. Zhao Y, Cui JG, Lukiw WJ (2006) Natural secretory products of human neural and microvessel endothelial cells: implications in pathogenic “spreading” and Alzheimer's disease. Mol Neurobiol 34:181–192

    Article  CAS  PubMed  Google Scholar 

  59. Bazan NG (2006) Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photo-receptors. Trends Neurosci 29:263–271

    Article  CAS  PubMed  Google Scholar 

  60. Bazan NG (2007) Omega-3 fatty acids, pro-inflammatory signaling and neuroprotection. Curr Opin Clin Nutr Metab Care 10:136–141

    Article  CAS  PubMed  Google Scholar 

  61. Lukiw WJ, Bazan NG (2010) Inflammatory, apoptotic and survival gene signaling in Alzheimer's disease. Molecular Neurobiology (in press)

  62. Lukiw WJ, Bazan NG (1998) Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer's disease superior temporal lobe neocortex. J Neurosci Res 53:583–592

    Article  CAS  PubMed  Google Scholar 

  63. Lukiw WJ, Zhao Y, Cui JG (2008) An NF-kappaB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem 283:31315–31322

    Article  CAS  PubMed  Google Scholar 

  64. Lukiw WJ, Bazan NG (2010) Inflammatory, Apoptotic, and Survival Gene Signaling in Alzheimer’s Disease: A Review on the Bioactivity of Neuroprotection D1 and Apoptosis. Mol Neurobiol. Apr 23 [Epub ahead of print]PMID: 20414817

Download references

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Walter J. Lukiw or Nicolas G. Bazan.

Additional information

Grant support: Alzheimer Association IIRG-09-131729, NS23002, NS046741 and EY005121.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Palacios-Pelaez, R., Lukiw, W.J. & Bazan, N.G. Omega-3 Essential Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease. Mol Neurobiol 41, 367–374 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Aging
  • Amyloid beta (Aβ) peptide
  • Beta-amyloid precursor protein (βAPP)
  • Cyclooxygenase-2 (COX-2)
  • Docosahexaenoic acid (DHA)
  • Hydroxynonenol (HNE)
  • Neuroprotectin D1 (NPD1)
  • Phospholipase A2
  • Polyunsaturated fatty acid (PUFA)