Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA

Simon C Dyall, Simon C Dyall

Abstract

Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer's disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.

Keywords: Alzheimer’s disease; Parkinson’s disease; aging; docosahexaenoic acid; docosapentaenoic acid; eicosapentaenoic acid; omega-3 fatty acids.

Figures

Figure 1
Figure 1
Synthesis of EPA, DPA and DHA from ALA. The longer chain omega-3 polyunsaturated fatty acids (PUFAs) are synthesized from ALA by a progressive series of enzymatic desaturation and chain elongation steps, initially in the endoplasmic reticulum. In the final stage tetracosahexaenoic acid (24:6n-3) is translocated to the peroxisome and is shorted by one cycle of the β-oxidation pathway to form DHA (22:6n-3). For further details refer to the text. Figure adapted from Dyall and Michael-Titus (2008).
Figure 2
Figure 2
Summary of the lipid mediators derived from (A) EPA, (B) DPA and (C) DHA. In the classical “canonical” pathway EPA is initially converted to the intermediate prostaglandin G2 (PGG2) by either COX-1 or -2 and then enzymatically to the 3 series prostaglandins, prostacylcins or thromboxanes. EPA can also be converted by 5-lipoxygenase (LOX) to 5-hydroperoxyeicosapenataenoic acid (5-H(p)EPE), which can then either be converted by 5-LOX to leukotriene A5 (LTA5) and then by Leukotriene A4 Hydrolase (LTA4) to leukotriene B5 (LTB5) or to 5-hydroxyeicosapentaenoic acid (5-HEPE), which is then converted into 5-oxo-EPA by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). EPA can also be sequentially converted by cytochrome P450 (CYP450) enzymes to 18R-hydroxyeicosapentaenoic acid (18R-HEPE) and then by 5-LOX to E-series resolvins (RvE). COX-2 can also convert EPA to the electrophilic fatty acid oxo-derivative electrophilic fatty acid oxo-derivates (EFOX)-D5, in a process enhanced by aspirin acetylation of COX-2. Aspirin acetylation of COX-2 also produces 18S- and 18R-hydroperoxyeicosapentaenoic acids (18S-, or 18R-HETE) from EPA, which are either converted by 5-LOX to aspirin-triggered 18S-resolvin E1 and resolvin E1 (AT-18S-RvE1 and AT-RvE1), respectively, or through an extra step by LTA4H to AT-18S-RvE2 and AT-RvE2. Analogous series of resolvins, maresins, and EFOXs produced from DPA to those from DHA have recently been identified; however, the nature of the enzymatic conversions remains to be elucidated. DHA is converted to 17S-hydroperoxydocosahexaenoic acid (17S-H(p)DHA) by 15-LOX, which is converted by 5-LOX to D-series resolvins (RvD), or enzymatically hydrolysed to (neuro)protectin D1 ((N)PD1. DHA can also be converted by 12 or 15-LOX via 14-hydroperoxydocosahexaenoic acid (14-H(p)DHA) to the maresins. DHA can also be converted by 5-LOX to 7-hydroxydocosahexaenoic acid (7-HDHA) and then by a dehydrogenase to 7-oxo-DHA, with 5-HEDH a likely candidate, or by COX-2 to EFOX-D6, which is enhanced by aspirin acetylation. Acetylation also produces 17R-hydroperoxyDHA, which can then be converted to aspirin triggered resolvins and protectins.

References

    1. Able J. A., Liu Y., Jandacek R., Rider T., Tso P., McNamara R. K. (2014). Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression. J. Psychiatr Res. 50, 42–50. 10.1016/j.jpsychires.2013.11.008
    1. Akbar M., Calderon F., Wen Z., Kim H. Y. (2005). Docosahexaenoic acid: a positive modulator of Akt signaling in neuronal survival. Proc. Natl. Acad. Sci. U S A 102, 10858–10863. 10.1073/pnas.0502903102
    1. Ames B. N. (2004). Delaying the mitochondrial decay of aging. Ann. N Y Acad. Sci. 1019, 406–411. 10.1196/annals.1297.073
    1. Anderton B. H. (2002). Ageing of the brain. Mech. Ageing Dev. 123, 811–817. 10.1016/S0047-6374(01)00426-2
    1. Anderson B. M., Ma D. W. (2009). Are all n-3 polyunsaturated fatty acids created equal? Lipids Health Dis. 8:33. 10.1186/1476-511x-8-33
    1. Arterburn L. M., Hall E. B., Oken H. (2006). Distribution, interconversion and dose response of n-3 fatty acids in humans. Am. J. Clin. Nutr. 83, 1467S–1476S.
    1. Astarita G., Jung K. M., Berchtold N. C., Nguyen V. Q., Gillen D. L., Head E., et al. . (2010). Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer’s disease. PLoS One 5:e12538. 10.1371/journal.pone.0012538
    1. Aursnes M., Tungen J. E., Vik A., Colas R., Cheng C. Y., Dalli J., et al. . (2014). Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions. J. Nat. Prod. 77, 910–916. 10.1021/np4009865
    1. Balas L., Guichardant M., Durand T., Lagarde M. (2014). Confusion between protectin D1 (PD1) and its isomer protectin DX (PDX). An overview on the dihydroxy-docosatrienes described to date. Biochimie 99, 1–7. 10.1016/j.biochi.2013.11.006
    1. Bannenberg G., Serhan C. N. (2010). Specialized pro-resolving lipid mediators in the inflammatory response: an update. Biochim. Biophys. Acta 1801, 1260–1273. 10.1016/j.bbalip.2010.08.002
    1. Barceló-Coblijn G., Murphy E. J. (2009). Alpha-linolenic acid and its conversion to longer chain n-3 fatty acids: benefits for human health and a role in maintaining tissue n-3 fatty acid levels. Prog. Lipid Res. 48, 355–374. 10.1016/j.plipres.2009.07.002
    1. Bazan N. G. (2013). The docosanoid neuroprotectin D1 induces homeostatic regulation of neuroinflammation and cell survival. Prostaglandins Leukot. Essent. Fatty Acids 88, 127–129. 10.1016/j.plefa.2012.08.008
    1. Bazan N. G., Molina M. F., Gordon W. C. (2011a). Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer’s and other neurodegenerative diseases. Annu. Rev. Nutr. 31, 321–351. 10.1146/annurev.nutr.012809.104635
    1. Bazan N. G., Musto A. E., Knott E. J. (2011b). Endogenous signaling by omega-3 docosahexaenoic acid-derived mediators sustains homeostatic synaptic and circuitry integrity. Mol. Neurobiol. 44, 216–222. 10.1007/s12035-011-8200-6
    1. Bliss T. V. P., Collingridge G. L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39. 10.1038/361031a0
    1. Bloch M. H., Hannestad J. (2012). Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol. Psychiatry 17, 1272–1282. 10.1038/mp.2011.100
    1. Boston P. F., Bennett A., Horrobin D. F., Bennett C. N. (2004). Ethyl-EPA in Alzheimer’s disease–a pilot study. Prostaglandins Leukot. Essent. Fatty Acids 71, 341–346. 10.1016/j.plefa.2004.07.001
    1. Bourre J.-M., Francois M., Youyou A., Dumont O., Piciotti M., Pascal G., et al. . (1989). The effects of dietary α-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. J. Nutr. 119, 1880–1892.
    1. Bousquet M., Saint-Pierre M., Julien C., Salem N., Jr., Cicchetti F., Calon F. (2008). Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson’s disease. FASEB J. 22, 1213–1225. 10.1096/fj.07-9677com
    1. Breder C. D., Dewitt D., Kraig R. P. (1995). Characterization of inducible cyclooxygenase in rat brain. J. Comp. Neurol. 355, 296–315. 10.1002/cne.903550208
    1. Brenna J. T., Diau G. Y. (2007). The influence of dietary docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition. Prostaglandins Leukot. Essent. Fatty Acids 77, 247–250. 10.1016/j.plefa.2007.10.016
    1. Brenna J. T., Salem N., Jr., Sinclair A. J., Cunnane S. C., International Society for the Study of Fatty Acids and Lipids, ISSFAL . (2009). alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot. Essent. Fatty Acids 80, 85–91. 10.1016/j.plefa.2009.01.004
    1. Brown A. J., Pang E., Roberts D. C. (1991). Erythrocyte eicosapentaenoic acid versus docosahexaenoic acid as a marker for fish and fish oil consumption. Prostaglandins Leukot. Essent. Fatty Acids 44, 103–106. 10.1016/0952-3278(91)90191-7
    1. Calderon F., Kim H. Y. (2004). Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J. Neurochem. 90, 979–988. 10.1111/j.1471-4159.2004.02520.x
    1. Camilleri A., Vassallo N. (2014). The centrality of mitochondria in the pathogenesis and treatment of Parkinson’s disease. CNS Neurosci. Ther. 20, 591–602. 10.1111/cns.12264
    1. Cansev M., Wurtman R. J. (2007). Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience 148, 421–431. 10.1016/j.neuroscience.2007.06.016
    1. Canugovi C., Misiak M., Ferrarelli L. K., Croteau D. L., Bohr V. A. (2013). The role of DNA repair in brain related disease pathology. DNA Repair (Amst) 12, 578–587. 10.1016/j.dnarep.2013.04.010
    1. Cao D., Kevala K., Kim J., Moon H.-S., Jun S. B., Lovinger D., et al. . (2009). Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J. Neurochem. 111, 510–521. 10.1111/j.1471-4159.2009.06335.x
    1. Cao D., Xue R., Xu J., Liu Z. (2005). Effects of docosahexaenoic acid on the survival and neurite outgrowth of rat cortical neurons in primary cultures. J. Nutr. Biochem. 16, 538–546. 10.1016/j.jnutbio.2005.02.002
    1. Cardoso H. D., dos Santos Junior E. F., de Santana D. F., Gonçalves-Pimentel C., Angelim M. K., Isaac A. R., et al. . (2014). Omega-3 deficiency and neurodegeneration in the substantia nigra: involvement of increased nitric oxide production and reduced BDNF expression. Biochim. Biophys. Acta 1840, 1902–1912. 10.1016/j.bbagen.2013.12.023
    1. Chen C. T., Domenichiello A. F., Trépanier M. O., Liu Z., Masoodi M., Bazinet R. P. (2013). The low levels of eicosapentaenoic acid in rat brain phospholipids are maintained via multiple redundant mechanisms. J. Lipid Res. 54, 2410–2422. 10.1194/jlr.M038505
    1. Chen C. T., Liu Z., Ouellet M., Calon F., Bazinet R. P. (2009). Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study. Prostaglandins Leukot. Essent. Fatty Acids 80, 157–163. 10.1016/j.plefa.2009.01.005
    1. Chouinard-Watkins R., Rioux-Perreault C., Fortier M., Tremblay-Mercier J., Zhang Y., Lawrence P., et al. . (2013). Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE epsilon4 allele. Br. J. Nutr. 110, 1751–1759. 10.1017/s0007114513001268
    1. Cipollina C., Salvatore S. R., Muldoon M. F., Freeman B. A., Schopfer F. J. (2014). Generation and dietary modulation of anti-inflammatory electrophilic omega-3 fatty acid derivatives. PLoS One 9:e94836. 10.1371/journal.pone.0094836
    1. Contreras M. A., Chang M. C. J., Rosenberger T. A., Greiner R. S., Myers C. S., Salem J., et al. . (2001). Chronic nutritional deprivation of n-3 alpha-linolenic acid does not affect n-6 arachidonic acid recycling within brain phospholipids of awake rats. J. Neurochem. 79, 1090–1099. 10.1046/j.1471-4159.2001.00658.x
    1. Corey E. J., Shih C., Cashman J. R. (1983). Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis. Proc. Natl. Acad. Sci. U S A 80, 3581–3584. 10.1073/pnas.80.12.3581
    1. Crawford M. A., Broadhurst C. L., Guest M., Nagar A., Wang Y., Ghebremeskel K., et al. . (2013). A quantum theory for the irreplaceable role of docosahexaenoic acid in neural cell signalling throughout evolution. Prostaglandins Leukot. Essent. Fatty Acids 88, 5–13. 10.1016/j.plefa.2012.08.005
    1. Crawford M. A., Casperd N. M., Sinclair A. J. (1976). The long chain metabolites of linoleic and linolenic acids in liver and brain in herbivores and carnivores. Comp. Biochem. Physiol. B 54B, 395–401. 10.1016/0305-0491(76)90264-9
    1. Cummings J. L., Morstorf T., Zhong K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6:37. 10.1186/alzrt269
    1. Cunnane S. C., Schneider J. A., Tangney C., Tremblay-Mercier J., Fortier M., Bennett D. A., et al. . (2012). Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J. Alzheimers Dis. 29, 691–697. 10.3233/JAD-2012-110629
    1. Dalli J., Colas R. A., Serhan C. N. (2013). Novel n-3 immunoresolvents: structures and actions. Sci. Rep. 3:1940. 10.1038/srep01940
    1. Darsalia V., Heldmann U., Lindvall O., Kokaia Z. (2005). Stroke-induced neurogenesis in aged brain. Stroke 36, 1790–1795. 10.1161/
    1. De Franceschi G., Frare E., Pivato M., Relini A., Penco A., Greggio E., et al. . (2011). Structural and morphological characterization of aggregated species of α-synuclein induced by docosahexaenoic acid. J. Biol. Chem. 286, 22262–22274. 10.1074/jbc.M110.202937
    1. Demar J. C., Jr., Lee H.-J., Ma K., Chang L., Bell J. M., Rapoport S. I., et al. . (2006). Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats. Biochim. Biophys. Acta 1761, 1050–1059. 10.1016/j.bbalip.2006.06.006
    1. Demar J. C., Jr., Ma K., Chang L., Bell J. M., Rapoport S. I. (2005). α-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid. J. Neurochem. 94, 1063–1076. 10.1111/j.1471-4159.2005.03258.x
    1. Denis I., Potier B., Heberden C., Vancassel S. (2015). Omega-3 polyunsaturated fatty acids and brain aging. Curr. Opin. Clin. Nutr. Metab. Care 18, 139–146. 10.1097/MCO.0000000000000141
    1. de Urquiza A. M., Liu S., Sjöberg M., Zetterström R. H., Griffiths W., Sjövall J., et al. . (2000). Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290, 2140–2144. 10.1126/science.290.5499.2140
    1. Drapeau E., Mayo W., Aurousseau C., Le Moal M., Piazza P. V., Abrous D. N. (2003). Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc. Natl. Acad. Sci. U S A 100, 14385–14390. 10.1073/pnas.2334169100
    1. Dyall S. C. (2010). Amyloid-beta peptide, oxidative stress and inflammation in Alzheimer’s disease: potential neuroprotective effects of omega-3 polyunsaturated fatty acids. Int. J. Alzheimers Dis. 2010:274128 10.4061/2010/274128
    1. Dyall S. C. (2011). Methodological issues and inconsistencies in the field of omega-3 fatty acids research. Prostaglandins Leukot. Essent. Fatty Acids 85, 281–285. 10.1016/j.plefa.2011.04.009
    1. Dyall S. C., Michael-Titus A. T. (2008). Neurological benefits of omega-3 fatty acids. Neuromolecular Med. 10, 219–235. 10.1007/s12017-008-8036-z
    1. Dyall S. C., Michael G. J., Michael-Titus A. T. (2010). Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. J. Neurosci. Res. 88, 2091–2102. 10.1002/jnr.22390
    1. Egea P. F., Mitschler A., Moras D. (2002). Molecular recognition of agonist ligands by RXRs. Mol. Endocrinol. 16, 987–997. 10.1210/me.16.5.987
    1. Ehninger D., Kempermann G. (2008). Neurogenesis in the adult hippocampus. Cell Tissue Res. 331, 243–250. 10.1007/s00441-007-0478-3
    1. Eldho N. V., Feller S. E., Tristram-Nagle S., Polozov I. V., Gawrisch K. (2003). Polyunsaturated docosahexaenoic vs docosapentaenoic acid differences in lipid matrix properties from the loss of one double bond. J. Am. Chem. Soc. 125, 6409–6421. 10.1021/ja029029o
    1. Emsley R., Niehaus D. J., Koen L., Oosthuizen P. P., Turner H. J., Carey P., et al. . (2006). The effects of eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo-controlled trial. Schizophr. Res. 84, 112–120. 10.1016/j.schres.2006.03.023
    1. Enslen M., Milon H., Malnoe A. (1991). Effect of low intake of n-3 fatty acids during development on brain phospholipid fatty acid composition and exploratory behavior in rats. Lipids 26, 203–208. 10.1007/bf02543972
    1. Fabelo N., Martin V., Santpere G., Marin R., Torrent L., Ferrer I., et al. . (2011). Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol. Med. 17, 1107–1118. 10.2119/molmed.2011.00119
    1. Farkas T., Kitajka K., Fodor E., Csengeri I., Lahdes E., Yeo Y. K., et al. . (2000). Docosahexaenoic acid-containing phospholipid molecular species in brains of vertebrates. Proc. Natl. Acad. Sci. U S A 97, 6362–6366. 10.1073/pnas.120157297
    1. Faulkner M. A. (2014). Safety overview of FDA-approved medications for the treatment of the motor symptoms of Parkinson’s disease. Expert Opin. Drug Saf. 13, 1055–1069. 10.1517/14740338.2014.931369
    1. Feart C., Peuchant E., Letenneur L., Samieri C., Montagnier D., Fourrier-Reglat A., et al. . (2008). Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City study. Am. J. Clin. Nutr. 87, 1156–1162.
    1. Fecchio C., De Franceschi G., Relini A., Greggio E., Dalla Serra M., Bubacco L., et al. . (2013). α-Synuclein oligomers induced by docosahexaenoic acid affect membrane integrity. PLoS One 8:e82732. 10.1371/journal.pone.0082732
    1. Fjell A. M., McEvoy L., Holland D., Dale A. M., Walhovd K. B., Alzheimer’s Disease Neuroimaging Initiative . (2014). What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog. Neurobiol. 117, 20–40. 10.1016/j.pneurobio.2014.02.004
    1. Franco-Iborra S., Vila M., Perier C. (2015). The Parkinson disease mitochondrial hypothesis: where are we at? Neuroscientist [Epub ahead of print]. 10.1177/1073858415574600
    1. Freund-Levi Y., Eriksdotter-Jönhagen M., Cederholm T., Basun H., Faxén-Irving G., Garlind A., et al. . (2006). Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63, 1402–1408. 10.1001/archneur.63.10.1402
    1. Galli C., Trzeciak H. I., Paoletti R. (1971). Effects of dietary fatty acids on the fatty acid composition of brain ethanolamine phosphoglyceride: reciprocal replacement of n-6 and n-3 polyunsaturated fatty acids. Biochim. Biophys. Acta 248, 449–454 10.1016/0005-2760(71)90233-5
    1. Garcia M. C., Ward G. R., Ma Y.-C., Salem N., Jr., Kim H.-Y. (1998). Effect of docosahexaenoic acid on the synthesis of phosphatidylserine in rat brain in microsomes and C6 glioma cells. J. Neurochem. 70, 24–30. 10.1046/j.1471-4159.1998.70010024.x
    1. Garda H. A., Bernasconi A. M., Brenner R. R. (1994). Comparison of structural and viscotrophic properties in hepatic microsomes and erythrocyte membranes of rats with essential fatty acid deficiency. J. Lipid Res. 35, 1367–1377.
    1. Ghasemi Fard S., Linderborg K. M., Turchini G. M., Sinclair A. J. (2014). Comparison of the bioavailability of docosapentaenoic acid (DPA, 22:5n-3) and eicosapentaenoic acid (EPA, 20:5n-3) in the rat. Prostaglandins Leukot. Essent. Fatty Acids 90, 23–26. 10.1016/j.plefa.2013.10.001
    1. Gorjão R., Azevedo-Martins A. K., Rodrigues H. G., Abdulkader F., Arcisio-Miranda M., Procopio J., et al. . (2009). Comparative effects of DHA and EPA on cell function. Pharmacol. Ther. 122, 56–64. 10.1016/j.pharmthera.2009.01.004
    1. Gregory M. K., Gibson R. A., Cook-Johnson R. J., Cleland L. G., James M. J. (2011). Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis. PLoS One 6:e29662. 10.1371/journal.pone.0029662
    1. Groeger A. L., Cipollina C., Cole M. P., Woodcock S. R., Bonacci G., Rudolph T. K., et al. . (2010). Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat. Chem. Biol. 6, 433–441. 10.1038/nchembio.367
    1. Hauser P. S., Ryan R. O. (2013). Impact of apolipoprotein E on Alzheimer’s disease. Curr. Alzheimer Res. 10, 809–817. 10.2174/15672050113109990156
    1. Holub B. J., Swidinsky P., Park E. (2011). Oral docosapentaenoic acid (22:5n-3) is differentially incorporated into phospholipid pools and differentially metabolized to eicosapentaenoic acid in tissues from young rats. Lipids 46, 399–407. 10.1007/s11745-011-3535-3
    1. Ikemoto A., Kobayashi T., Watanabe S., Okuyama H. (1997). Membrane fatty acid modifications of PC12 cells by arachidonate or docosahexaenoate affect neurite outgrowth but not norepinephrine release. Neurochem Res. 22, 671–678. 10.1023/A:1027393724676
    1. Jiao J., Li Q., Chu J., Zeng W., Yang M., Zhu S. (2014). Effect of n-3 PUFA supplementation on cognitive function throughout the life span from infancy to old age: a systematic review and meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 100, 1422–1436. 10.3945/ajcn.114.095315
    1. Julien C., Berthiaume L., Hadj-Tahar A., Rajput A. H., Bédard P. J., Di Paolo T., et al. . (2006). Postmortem brain fatty acid profile of levodopa-treated Parkinson disease patients and parkinsonian monkeys. Neurochem. Int. 48, 404–414. 10.1016/j.neuint.2005.12.002
    1. Katakura M., Hashimoto M., Okui T., Shahdat H. M., Matsuzaki K., Shido O. (2013). Omega-3 polyunsaturated Fatty acids enhance neuronal differentiation in cultured rat neural stem cells. Stem Cells Int. 2013:490476. 10.1155/2013/490476
    1. Katakura M., Hashimoto M., Shahdat H. M., Gamoh S., Okui T., Matsuzaki K., et al. . (2009). Docosahexaenoic acid promotes neuronal differentiation by regulating basic helix-loop-helix transcription factors and cell cycle in neural stem cells. Neuroscience 160, 651–660. 10.1016/j.neuroscience.2009.02.057
    1. Katan M. B., Deslypere J. P., van Birgelen A. P., Penders M., Zegwaard M. (1997). Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes and adipose tissue: an 18-month controlled study. J. Lipid Res. 38, 2012–2022.
    1. Kaufmann W. E., Worley P. F., Pegg J., Bremer M., Isakson P. (1996). COX-2, a synaptically induced enzyme, is expresses by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc. Natl. Acad. Sci. U S A 93, 2317–2321. 10.1073/pnas.93.6.2317
    1. Kaur G., Begg D. P., Barr D., Garg M., Cameron-Smith D., Sinclair A. J. (2010). Short-term docosapentaenoic acid (22:5 n-3) supplementation increases tissue docosapentaenoic acid, DHA and EPA concentrations in rats. Br. J. Nutr. 103, 32–37. 10.1017/s0007114509991334
    1. Kaur G., Cameron-Smith D., Garg M., Sinclair A. J. (2011). Docosapentaenoic acid (22:5n-3): a review of its biological effects. Prog. Lipid Res. 50, 28–34. 10.1016/j.plipres.2010.07.004
    1. Kaur G., Molero J. C., Weisinger H. S., Sinclair A. J. (2013). Orally administered [14C]DPA and [14C]DHA are metabolised differently to [14C]EPA in rats. Br. J. Nutr. 109, 441–448. 10.1017/s0007114512001419
    1. Kawakita E., Hashimoto M., Shido O. (2006). Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 139, 991–997. 10.1016/j.neuroscience.2006.01.021
    1. Kelly L., Grehan B., Chiesa A. D., O’Mara S. M., Downer E., Sahyoun G., et al. . (2011). The polyunsaturated fatty acids, EPA and DPA exert a protective effect in the hippocampus of the aged rat. Neurobiol. Aging 32, 2318.e1–2318.e15. 10.1016/j.neurobiolaging.2010.04.001
    1. Kim H. Y., Bigelow J., Kevala J. H. (2004). Substrate preference in phosphatidylserine biosynthesis for docosahexaenoic acid containing species. Biochemistry 43, 1030–1036. 10.1021/bi035197x
    1. Kim H. Y., Huang B. X., Spector A. A. (2014a). Phosphatidylserine in the brain: metabolism and function. Prog. Lipid Res. 56C, 1–18. 10.1016/j.plipres.2014.06.002
    1. Kim W. S., Kågedal K., Halliday G. M. (2014b). Alpha-synuclein biology in Lewy body diseases. Alzheimers Res. Ther. 6:73. 10.1186/s13195-014-0073-2
    1. Kuhn H. G., Dickinson-Anson H., Gage F. H. (1996). Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci. 16, 2027–2033.
    1. Kulmacz R. J., van der Donk W. A., Tsai A.-L. (2003). Comparison of the properties of prostaglandin H synthase-1 and -2. Prog. Lipid Res. 42, 377–404. 10.1016/s0163-7827(03)00023-7
    1. Lee C. H., Hajra A. K. (1991). Molecular species of diacylglycerols and phosphoglycerides and the postmortem changes in the molecular species of diacylglycerols in rat brains. J. Neurochem. 56, 370–379. 10.1111/j.1471-4159.1991.tb08161.x
    1. Lee L. K., Shahar S., Chin A. V., Yusoff N. A. (2013). Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology (Berl) 225, 605–612. 10.1007/s00213-012-2848-0
    1. Lemaitre R. N., Tanaka T., Tang W., Manichaikul A., Foy M., Kabagambe E. K., et al. . (2011). Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE consortium. PLoS Genet. 7:e1002193. 10.1371/journal.pgen.1002193
    1. Lengqvist J., Mata De Urquiza A., Bergman A. C., Willson T. M., Sjövall J., Perlmann T., et al. . (2004). Polyunsaturated fatty acids including docosahexaenoic and arachidonic acid bind to the retinoid X receptor alpha ligand-binding domain. Mol. Cell. Proteomics 3, 692–703. 10.1074/mcp.m400003-mcp200
    1. Lim S. Y., Hoshiba J., Salem N., Jr. (2005). An extraordinary degree of structural specificity is required in neural phospholipids for optimal brain function: n-6 docosapentaenoic acid substitution for docosahexaenoic acid leads to a loss in spatial task performance. J. Neurochem. 95, 848–857. 10.1111/j.1471-4159.2005.03427.x
    1. Lin P. Y., Chiu C. C., Huang S. Y., Su K. P. (2012a). A meta-analytic review of polyunsaturated fatty acid compositions in dementia. J. Clin. Psychiatry 73, 1245–1254. 10.4088/JCP.11r07546
    1. Lin P. Y., Mischoulon D., Freeman M. P., Matsuoka Y., Hibbeln J., Belmaker R. H., et al. . (2012b). Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation and severity of depression. Mol. Psychiatry 17, 1161–1163; author reply 1163–1167. 10.1038/mp.2012.111
    1. Linderborg K. M., Kaur G., Miller E., Meikle P. J., Larsen A. E., Weir J. M., et al. . (2013). Postprandial metabolism of docosapentaenoic acid (DPA, 22:5n-3) and eicosapentaenoic acid (EPA, 20:5n-3) in humans. Prostaglandins Leukot. Essent. Fatty Acids 88, 313–319. 10.1016/j.plefa.2013.01.010
    1. Little S. J., Lynch M. A., Manku M., Nicolaou A. (2007). Docosahexaenoic acid-induced changes in phospholipids in cortex of young and aged rats: a lipidomic analysis. Prostaglandins Leukot. Essent. Fatty Acids 77, 155–162. 10.1016/j.plefa.2007.08.009
    1. Lloret A., Fuchsberger T., Giraldo E., Viña J. (2015). Molecular mechanisms linking amyloid β toxicity and Tau hyperphosphorylation in Alzheimer’s disease. Free Radic. Biol. Med. [Epub ahead of print]. 10.1016/j.freeradbiomed.2015.02.028
    1. Luchtman D. W., Meng Q., Song C. (2012). Ethyl-eicosapentaenoate (E-EPA) attenuates motor impairments and inflammation in the MPTP-probenecid mouse model of Parkinson’s disease. Behav. Brain Res. 226, 386–396. 10.1016/j.bbr.2011.09.033
    1. Luchtman D. W., Meng Q., Wang X., Shao D., Song C. (2013). ω-3 fatty acid eicosapentaenoic acid attenuates MPP+-induced neurodegeneration in fully differentiated human SH-SY5Y and primary mesencephalic cells. J. Neurochem. 124, 855–868. 10.1111/jnc.12068
    1. Lynch M. A. (2004). Long-term potentiation and memory. Physiol. Rev. 84, 87–136. 10.1152/physrev.00014.2003
    1. Lynch A. M., Loane D. J., Minogue A. M., Clarke R. M., Kilroy D., Nally R. E., et al. . (2007). Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol. Aging 28, 845–855. 10.1016/j.neurobiolaging.2006.04.006
    1. Maher F. O., Martin D. S., Lynch M. A. (2004). Increased IL-1β in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol. Aging 25, 795–806. 10.1016/j.neurobiolaging.2003.08.007
    1. Mandhair H. K., Fincham R. E. A., Opacka-Juffry J., Dyall S. C., Molina-Holgado F. (2013). “Cannabinoid signalling and IL-1β are critical mediators regulating omega-3 PUFAs neural stem cell fate decisions,” in 6th European Workshop on Cannabinoid Research. Proceedings of the British Pharmacological Society (Dublin, Ireland). Available online at:
    1. Martin D. S., Lonergan P. E., Boland B., Fogarty M. P., Brady M., Horrobin D. F., et al. . (2002). Apoptotic changes in the aged brain are triggered by interleukin-1beta-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J. Biol. Chem. 277, 34239–34246. 10.1074/jbc.m205289200
    1. McGahon B. M., Martin D. S., Horrobin D. F., Lynch M. A. (1999). Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids. Neuroscience 94, 305–314. 10.1016/s0306-4522(99)00219-5
    1. Meng Q., Luchtman D. W., El Bahh B., Zidichouski J. A., Yang J., Song C. (2010). Ethyl-eicosapentaenoate modulates changes in neurochemistry and brain lipids induced by parkinsonian neurotoxin 1-methyl-4-phenylpyridinium in mouse brain slices. Eur. J. Pharmacol. 649, 127–134. 10.1016/j.ejphar.2010.09.046
    1. Metherel A. H., Armstrong J. M., Patterson A. C., Stark K. D. (2009). Assessment of blood measures of n-3 polyunsaturated fatty acids with acute fish oil supplementation and washout in men and women. Prostaglandins Leukot. Essent. Fatty Acids 81, 23–29. 10.1016/j.plefa.2009.05.018
    1. Miller E., Kaur G., Larsen A., Loh S. P., Linderborg K., Weisinger H. S., et al. . (2013). A short-term n-3 DPA supplementation study in humans. Eur. J. Nutr. 52, 895–904. 10.1007/s00394-012-0396-3
    1. Minogue A. M., Lynch A. M., Loane D. J., Herron C. E., Lynch M. A. (2007). Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J. Neurochem. 103, 914–926. 10.1111/j.1471-4159.2007.04848.x
    1. Moore S. A., Hurt E., Yoder E., Sprecher H., Spector A. A. (1995). Docosahexaenoic acid synthesis in human skin fibroblasts involves peroxisomal retroconversion of tetracosahexaenoic acid. J. Lipid Res. 36, 2433–2443.
    1. Mozaffarian D., Wu J. H. (2012). (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J. Nutr. 142, 614S–625S. 10.3945/jn.111.149633
    1. Nording M. L., Yang J., Georgi K., Hegedus Karbowski C., German J. B., Weiss R. H., et al. . (2013). Individual variation in lipidomic profiles of healthy subjects in response to omega-3 Fatty acids. PLoS One 8:e76575. 10.1371/journal.pone.0076575
    1. Ouellet M., Emond V., Chen C. T., Julien C., Bourasset F., Oddo S., et al. . (2009). Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: an in situ cerebral perfusion study. Neurochem. Int. 55, 476–482. 10.1016/j.neuint.2009.04.018
    1. Parent J. M., Yu T. W., Leibowitz R. T., Geschwind D. H., Sloviter R. S., Lowenstein D. H. (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci. 17, 3727–3738.
    1. Perluigi M., Swomley A. M., Butterfield D. A. (2014). Redox proteomics and the dynamic molecular landscape of the aging brain. Ageing Res. Rev. 13, 75–89. 10.1016/j.arr.2013.12.005
    1. Plourde M., Vohl M. C., Vandal M., Couture P., Lemieux S., Cunnane S. C. (2009). Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men. Br. J. Nutr. 102, 1121–1124. 10.1017/s000711450938215x
    1. Quinn J. F., Raman R., Thomas R. G., Yurko-Mauro K., Nelson E. B., Van Dyck C., et al. . (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304, 1903–1911. 10.1001/jama.2010.1510
    1. Rashid M. A., Katakura M., Kharebava G., Kevala K., Kim H. Y. (2013). N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J. Neurochem. 125, 869–884. 10.1111/jnc.12255
    1. Robson L. G., Dyall S., Sidloff D., Michael-Titus A. T. (2010). Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals. Neurobiol. Aging 31, 678–687. 10.1016/j.neurobiolaging.2008.05.027
    1. Rowlinson S. W., Crews B. C., Goodwin D. C., Schneider C., Gierse J. K., Marnett L. J. (2000). Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. J. Biol. Chem. 275, 6586–6591. 10.1074/jbc.275.9.6586
    1. Russell F. D., Bürgin-Maunder C. S. (2012). Distinguishing health benefits of eicosapentaenoic and docosahexaenoic acids. Mar. Drugs 10, 2535–2559. 10.3390/md10112535
    1. Samadi P., Grégoire L., Rouillard C., Bédard P. J., Di Paolo T., Lévesque D. (2006). Docosahexaenoic acid reduces Levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys. Ann. Neurol. 59, 282–288. 10.1002/ana.20738
    1. Samieri C., Féart C., Letenneur L., Dartigues J. F., Pérès K., Auriacombe S., et al. . (2008). Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk. Am. J. Clin. Nutr. 88, 714–721.
    1. Samieri C., Féart C., Proust-Lima C., Peuchant E., Dartigues J. F., Amieva H., et al. . (2011). ω-3 fatty acids and cognitive decline: modulation by ApoEepsilon4 allele and depression. Neurobiol. Aging 32, 2317.e13–2317.e22. 10.1016/j.neurobiolaging.2010.03.020
    1. Samieri C., Maillard P., Crivello F., Proust-Lima C., Peuchant E., Helmer C., et al. . (2012). Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology 79, 642–650. 10.1212/WNL.0b013e318264e394
    1. Sanchez-Guajardo V., Tentillier N., Romero-Ramos M. (2015). The relation between α-synuclein and microglia in Parkinson’s disease: recent developments. Neuroscience [Epub ahead of print]. 10.1016/j.neuroscience.2015.02.008
    1. Schaefer E. J., Bongard V., Beiser A. S., Lamon-Fava S., Robins S. J., Au R., et al. . (2006). Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease. Arch. Neurol. 63, 1545–1550. 10.1001/archneur.63.11.1545
    1. Selkoe D., Mandelkow E., Holtzman D. (2012). Deciphering Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a011460. 10.1101/cshperspect.a011460
    1. Serhan C. N., Chiang N. (2013). Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 13, 632–640. 10.1016/j.coph.2013.05.012
    1. Serhan C. N., Chiang N., Van Dyke T. E. (2008). Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8, 349–361. 10.1038/nri2294
    1. Serhan C. N., Dalli J., Colas R. A., Winkler J. W., Chiang N. (2015). Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim. Biophys. Acta 1851, 397–413. 10.1016/j.bbalip.2014.08.006
    1. Serhan C. N., Hong S., Gronert K., Colgan S. P., Devchand P. R., Mirick G., et al. . (2002). Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037. 10.1084/jem.20020760
    1. Serhan C. N., Yang R., Martinod K., Kasuga K., Pillai P. S., Porter T. F., et al. . (2009). Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J. Exp. Med. 206, 15–23. 10.1084/jem.20081880
    1. Serini S., Bizzarro A., Piccioni E., Fasano E., Rossi C., Lauria A., et al. . (2012). EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer’s patients. Curr. Alzheimer Res. 9, 913–923. 10.2174/156720512803251147
    1. Sinn N., Milte C. M., Street S. J., Buckley J. D., Coates A. M., Petkov J., et al. . (2012). Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br. J. Nutr. 107, 1682–1693. 10.1017/s0007114511004788
    1. Smith W. L., Dewitt D. L., Garavito R. M. (2000). Cyclooxygenases: structural, cellular and molecular biology. Annu. Rev. Biochem. 69, 145–182. 10.1146/annurev.biochem.69.1.145
    1. Stillwell W., Shaikh S. R., Zerouga M., Siddiqui R., Wassall S. R. (2005). Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reprod. Nutr. Dev. 45, 559–579. 10.1051/rnd:2005046
    1. Stillwell W., Wassall S. R. (2003). Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem. Phys. Lipids 126, 1–27. 10.1016/s0009-3084(03)00101-4
    1. Sublette M. E., Ellis S. P., Geant A. L., Mann J. J. (2011). Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 72, 1577–1584. 10.4088/JCP.10m06634
    1. Svennerholm L., Boström K., Jungbjer B. (1997). Changes in weight and compositions of major membrane components of human brain during the span of adult human life of Swedes. Acta Neuropathol. 94, 345–352. 10.1007/s004010050717
    1. Takagi Y., Nozaki K., Takahashi J., Yodoi J., Ishikawa M., Hashimoto N. (1999). Proliferation of neuronal precursor cells in the dentate gyrus is accelerated after transient forebrain ischemia in mice. Brain Res. 831, 283–287. 10.1016/s0006-8993(99)01411-0
    1. Tan Z. S., Harris W. S., Beiser A. S., Au R., Himali J. J., Debette S., et al. . (2012). Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology 78, 658–664. 10.1212/WNL.0b013e318249f6a9
    1. Tu W. C., Mühlhäusler B. S., Yelland L. N., Gibson R. A. (2013). Correlations between blood and tissue omega-3 LCPUFA status following dietary ALA intervention in rats. Prostaglandins Leukot. Essent. Fatty Acids 88, 53–60. 10.1016/j.plefa.2012.04.005
    1. Tungen J. E., Aursnes M., Dalli J., Arnardottir H., Serhan C. N., Hansen T. V. (2014). Total synthesis of the anti-inflammatory and pro-resolving lipid mediator MaR1n-3 DPA utilizing an sp(3) -sp(3) Negishi cross-coupling reaction. Chemistry 20, 14575–14578. 10.1002/chem.201404721
    1. Ward A., Crean S., Mercaldi C. J., Collins J. M., Boyd D., Cook M. N., et al. . (2012). Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis. Neuroepidemiology 38, 1–17. 10.1159/000334607
    1. Wassall S. R., Stillwell W. (2008). Docosahexaenoic acid domains: the ultimate non-raft membrane domain. Chem. Phys. Lipids 153, 57–63. 10.1016/j.chemphyslip.2008.02.010
    1. Whelan J. (2009). Dietary stearidonic acid is a long chain (n-3) polyunsaturated fatty acid with potential health benefits. J. Nutr. 139, 5–10. 10.3945/jn.108.094268
    1. Williams J. A., Batten S. E., Harris M., Rockett B. D., Shaikh S. R., Stillwell W., et al. . (2012). Docosahexaenoic and eicosapentaenoic acids segregate differently between raft and nonraft domains. Biophys. J. 103, 228–237. 10.1016/j.bpj.2012.06.016
    1. Xie A., Gao J., Xu L., Meng D. (2014). Shared mechanisms of neurodegeneration in Alzheimer’s disease and Parkinson’s disease. Biomed. Res. Int. 2014:648740. 10.1155/2014/648740
    1. Yakunin E., Loeb V., Kisos H., Biala Y., Yehuda S., Yaari Y., et al. . (2012). α-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson’s disease. Brain Pathol. 22, 280–294. 10.1111/j.1750-3639.2011.00530.x
    1. Yamagata K., Andreasson K. I., Kaufmann W. E., Barnes C. A., Worley P. F. (1993). Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11, 371–386. 10.1016/0896-6273(93)90192-t
    1. Yanes O., Clark J., Wong D. M., Patti G. J., Sánchez-Ruiz A., Benton H. P., et al. . (2010). Metabolic oxidation regulates embryonic stem cell differentiation. Nat. Chem. Biol. 6, 411–417. 10.1038/nchembio.364
    1. Yurko-Mauro K., McCarthy D., Rom D., Nelson E. B., Ryan A. S., Blackwell A., et al. . (2010). Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 6, 456–464. 10.1016/j.jalz.2010.01.013

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa