The brain is especially enriched with the two polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid. Although, quantitatively speaking, they are primarily esterified to brain phophospholipids, they can be released from the membrane and transformed into highly biologically active molecules.
The mechanisms by which the brain takes up polyunsaturated fatty acids are not clear and remain controversial. Candidate plasma pools include phospholipids as part of lipoproteins, unesterified fatty acids and lysophospholipids. Because polyunsaturated fatty acids are derived from the diet, changes in their intakes can alter brain levels and thus the activity of pathways regulated by polyunsaturated fatty acids in the brain.
In response to neuroreceptor activation, fatty acids are released from the membrane and participate in cell signalling.
So far, polyunsaturated fatty acids and their biologically active derivatives have been shown to regulate cell survival, neurogenesis, brain inflammation and synaptic function.
Altered fatty acid signalling has been implicated in mood disorders, cognition, Alzheimer's disease, schizophrenia and other conditions. Research using animal models has shown promise in targeting brain polyunsaturated fatty acid metabolism with diet or drugs; however, translational studies often do not yield statistically significant results. New methods to target brain polyunsaturated metabolism are emerging as novel approaches to treat brain disorders.
The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
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Rapoport, S. I. Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot. Essent. Fatty Acids 88, 79–85 (2013).
Mitchell, R. W. & Hatch, G. M. Fatty acid transport into the brain: of fatty acid fables and lipid tails. Prostaglandins Leukot. Essent. Fatty Acids 85, 293–302 (2011).
Nguyen, L. N. et al. Mfsd2a is a transporter for the essential ω-3 fatty acid docosahexaenoic acid. Nature 509, 503–506 (2014).
Chen, C. T. & Bazinet, R. P. β-oxidation and rapid metabolism, but not uptake regulate brain eicosapentaenoic acid levels. Prostaglandins Leukot. Essent. Fatty Acids http://dx.doi.org/10.1016/j.plefa.2014.05.007 (2014).
Goldberg, I. J., Eckel, R. H. & Abumrad, N. A. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. J. Lipid Res. 50 (Suppl.), S86–S90 (2009).
Chen, S. & Subbaiah, P. V. Regioisomers of phosphatidylcholine containing DHA and their potential to deliver DHA to the brain: role of phospholipase specificities. Lipids 48, 675–686 (2013).
Hamilton, J. A. & Brunaldi, K. A model for fatty acid transport into the brain. J. Mol. Neurosci. 33, 12–17 (2007).
Jia, Z., Pei, Z., Maiguel, D., Toomer, C. J. & Watkins, P. A. The fatty acid transport protein (FATP) family: very long chain acyl-CoA synthetases or solute carriers? J. Mol. Neurosci. 33, 25–31 (2007).
Mashek, D. G. & Coleman, R. A. Cellular fatty acid uptake: the contribution of metabolism. Curr. Opin. Lipidol. 17, 274–278 (2006).
Xu, S., Jay, A., Brunaldi, K., Huang, N. & Hamilton, J. A. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 52, 7254–7261 (2013).
Neculai, D. et al. Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36. Nature 504, 172–176 (2013).
Kuipers, R. S. et al. Fetal intrauterine whole body linoleic, arachidonic and docosahexaenoic acid contents and accretion rates. Prostaglandins Leukot. Essent. Fatty Acids 86, 13–20 (2012).
Hadley, K. B., Ryan, A. S., Nelson, E. B. & Salem, N. An assessment of dietary docosahexaenoic acid requirements for brain accretion and turnover during early childhood. World Rev. Nutr. Dietet. 99, 97–104 (2009).
Innis, S. M. Dietary ω 3 fatty acids and the developing brain. Brain Res. 1237, 35–43 (2008).
Lauritzen, L. & Carlson, S. E. Maternal fatty acid status during pregnancy and lactation and relation to newborn and infant status. Maternal Child Nutr. 7 (Suppl. 2), 41–58 (2011).
Makrides, M., Anderson, A., Gibson, R. A. & Collins, C. T. Improving the neurodevelopmental outcomes of low-birthweight infants. Nestle Nutr. Institute Workshop Series 74, 211–221 (2013).
Carver, J. D., Benford, V. J., Han, B. & Cantor, A. B. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res. Bull. 56, 79–85 (2001).
Rapoport, S. I., Rao, J. S. & Igarashi, M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot. Essent. Fatty Acids 77, 251–261 (2007).
Watkins, P. A. Fatty acid activation. Progress Lipid Res. 36, 55–83 (1997).
Mashek, D. G., Li, L. O. & Coleman, R. A. Long-chain acyl-CoA synthetases and fatty acid channeling. Future Lipidol. 2, 465–476 (2007).
DiRusso, C. C. et al. Comparative biochemical studies of the murine fatty acid transport proteins (FATP) expressed in yeast. J. Biol. Chem. 280, 16829–16837 (2005).
Liu, R. Z., Mita, R., Beaulieu, M., Gao, Z. & Godbout, R. Fatty acid binding proteins in brain development and disease. Int. J. Dev. Biol. 54, 1229–1239 (2010).
Eto, M., Shindou, H. & Shimizu, T. A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids. Biochem. Biophys. Res. Commun. 443, 718–724 (2014).
Vannucci, S. & Hawkins, R. Substrates of energy metabolism of the pituitary and pineal glands. J. Neurochem. 41, 1718–1725 (1983).
Schonfeld, P. & Reiser, G. Why does brain metabolism not favor burning of fatty acids to provide energy? - Reflections on disadvantages of the use of free fatty acids as fuel for brain. J. Cerebral Blood Flow Metabolism 33, 1493–1499 (2013).
Speijer, D. Oxygen radicals shaping evolution: why fatty acid catabolism leads to peroxisomes while neurons do without it: FADH(2)/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation. BioEssays 33, 88–94 (2011).
Chen, C. T. et al. Inhibiting mitochondrial β-oxidation selectively reduces levels of nonenzymatic oxidative polyunsaturated fatty acid metabolites in the brain. J. Cerebral Blood Flow Metabolism 34, 376–379 (2014).
Burke, J. E. & Dennis, E. A. Phospholipase A2 structure/function, mechanism, and signaling. J. Lipid Res. 50 (Suppl.), S237–242 (2009).
Contreras, M. A. & Rapoport, S. I. Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues. Curr. Opin. Lipidol. 13, 267–272 (2002).
Strokin, M., Sergeeva, M. & Reiser, G. Role of Ca2+-independent phospholipase A2 and n-3 polyunsaturated fatty acid docosahexaenoic acid in prostanoid production in brain: perspectives for protection in neuroinflammation. Int. J. Dev. Neurosci. 22, 551–557 (2004).
Green, J. T., Orr, S. K. & Bazinet, R. P. The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids. J. Lipid Res. 49, 939–944 (2008).
Purdon, A. D., Rosenberger, T. A., Shetty, H. U. & Rapoport, S. I. Energy consumption by phospholipid metabolism in mammalian brain. Neurochem. Res. 27, 1641–1647 (2002).
Vial, D. & Piomelli, D. Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2. J. Neurochem. 64, 2765–2772 (1995).
Felder, C. C., Williams, H. L. & Axelrod, J. A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release. Proc. Natl Acad. Sci. USA 88, 6477–6480 (1991).
Felder, C. C., Kanterman, R. Y., Ma, A. L. & Axelrod, J. Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc. Natl Acad. Sci. USA 87, 2187–2191 (1990).
Dumuis, A., Sebben, M., Haynes, L., Pin, J. P. & Bockaert, J. NMDA receptors activate the arachidonic acid cascade system in striatal neurons. Nature 336, 68–70 (1988).
Axelrod, J. Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem. Soc. Trans. 18, 503–507 (1990).
Rapoport, S. I. Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade. ACS Chem. Neurosci. 5, 459–467 (2014).
Bazan, N. G., Molina, M. F. & Gordon, W. C. Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu. Rev. Nutr. 31, 321–351 (2011).
Basselin, M., Ramadan, E. & Rapoport, S. I. Imaging brain signal transduction and metabolism via arachidonic and docosahexaenoic acid in animals and humans. Brain Res. Bull. 87, 154–171 (2012).
Murphy, E. J. Brain fixation for analysis of brain lipid-mediators of signal transduction and brain eicosanoids requires head-focused microwave irradiation: an historical perspective. Prostaglandins Other Lipid Mediators 91, 63–67 (2010). A detailed review of the important, but underappreciated, use of microwave fixation to measure biologically active lipids in the brain.
Serhan, C. N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014). A recent overview of lipid mediator biology, including its history and role in resolution and future directions.
Bosetti, F. Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J. Neurochem. 102, 577–586 (2007).
Farooqui, A. A., Horrocks, L. A. & Farooqui, T. Modulation of inflammation in brain: a matter of fat. J. Neurochem. 101, 577–599 (2007).
Orr, S. K. et al. Unesterified docosahexaenoic acid is protective in neuroinflammation. J. Neurochem. 127, 378–393 (2013).
Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).
Marcheselli, V. L. et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807–43817 (2003). The first paper to show that NPD1 is biologically active in the brain.
Thambisetty, M. et al. The utility of (11)C-arachidonate PET to study in vivo dopaminergic neurotransmission in humans. J. Cereb. Blood Flow Metab. 32, 676–684 (2012).
Lam, T. K., Schwartz, G. J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nature Neurosci. 8, 579–584 (2005).
Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).
Hohmann, A. G. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005).
Salem, N. Jr, Litman, B., Kim, H. Y. & Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36, 945–959 (2001). An older, but important, review of brain lipid chemistry and the candidate mechanisms of action of DHA.
Gawrisch, K., Eldho, N. V. & Holte, L. L. The structure of DHA in phospholipid membranes. Lipids 38, 445–452 (2003).
Shaikh, S. R. & Teague, H. N-3 fatty acids and membrane microdomains: from model membranes to lymphocyte function. Prostaglandins Leukot. Essent. Fatty Acids 87, 205–208 (2012).
Rao, J. S., Lee, H. J., Rapoport, S. I. & Bazinet, R. P. Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? Mol. Psychiatry 13, 585–596 (2008).
Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164–174 (2014).
Stella, N. Endocannabinoid signaling in microglial cells. Neuropharmacology 56 (Suppl. 1), 244–253 (2009).
Castillo, P. E., Younts, T. J., Chavez, A. E. & Hashimotodani, Y. Endocannabinoid signaling and synaptic function. Neuron 76, 70–81 (2012).
Grueter, B. A., Brasnjo, G. & Malenka, R. C. Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nature Neurosci. 13, 1519–1525 (2010).
Berger, A. et al. Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc. Natl Acad. Sci. USA 98, 6402–6406 (2001). The first study to show that diet can influence brain fatty acid ethanolamides.
Piscitelli, F. et al. Effect of dietary krill oil supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice. Nutr. Metab. 8, 51 (2011).
Watanabe, S., Doshi, M. & Hamazaki, T. n-3 polyunsaturated fatty acid (PUFA) deficiency elevates and n-3 PUFA enrichment reduces brain 2-arachidonoylglycerol level in mice. Prostaglandins Leukot Essent. Fatty Acids 69, 51–59 (2003).
Hutchins, H. L., Li, Y., Hannon, K. & Watkins, B. A. Eicosapentaenoic acid decreases expression of anandamide synthesis enzyme and cannabinoid receptor 2 in osteoblast-like cells. J. Nutr. Biochem. 22, 195–200 (2011).
Larrieu, T., Madore, C., Joffre, C. & Laye, S. Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice. J. Physiol. Biochem. 68, 671–681 (2012).
Lafourcade, M. et al. Nutritional ω-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nature Neurosci. 14, 345–350 (2011). In this paper, brain DHA is shown to regulate endocannabinoid-dependant synaptic plasticity through the impairment of the CB1 receptor signalling pathway.
Calon, F. et al. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 43, 633–645 (2004). A landmark paper demonstrating that DHA decreases β-amyloid in a mouse model of Alzheimer's disease.
Calon, F. et al. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease. Eur. J. Neurosci. 22, 617–626 (2005).
Davletov, B., Connell, E. & Darios, F. Regulation of SNARE fusion machinery by fatty acids. Cell. Mol. Life Sci. 64, 1597–1608 (2007).
Pongrac, J. L., Slack, P. J. & Innis, S. M. Dietary polyunsaturated fat that is low in (n-3) and high in (n-6) fatty acids alters the SNARE protein complex and nitrosylation in rat hippocampus. J. Nutr. 137, 1852–1856 (2007).
Darios, F. & Davletov, B. ω-3 and ω-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440, 813–817 (2006).
Mazelova, J., Ransom, N., Astuto-Gribble, L., Wilson, M. C. & Deretic, D. Syntaxin 3 and SNAP-25 pairing, regulated by ω-3 docosahexaenoic acid, controls the delivery of rhodopsin for the biogenesis of cilia-derived sensory organelles, the rod outer segments. J. Cell Sci. 122, 2003–2013 (2009).
Mathieu, G. et al. DHA enhances the noradrenaline release by SH-SY5Y cells. Neurochem. Int. 56, 94–100 (2010).
Fedorova, I. & Salem, N. Jr. ω-3 fatty acids and rodent behavior. Prostaglandins Leukot. Essent. Fatty Acids 75, 271–289 (2006).
Kim, H. Y., Akbar, M., Lau, A. & Edsall, L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J. Biol. Chem. 275, 35215–35223 (2000).
Calderon, F. & Kim, H. Y. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J. Neurochem. 90, 979–988 (2004).
Garcia, M. C., Ward, G., Ma, Y. C., Salem, N. Jr & Kim, H. Y. Effect of docosahexaenoic acid on the synthesis of phosphatidylserine in rat brain in microsomes and C6 glioma cells. J. Neurochem. 70, 24–30 (1998).
Kim, H. Y. & Spector, A. A. Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function. Prostaglandins Leukot. Essent. Fatty Acids 88, 121–125 (2013).
Kim, H. Y., Spector, A. A. & Xiong, Z. M. A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Other Lipid Mediators 96, 114–120 (2011).
Rashid, M. A., Katakura, M., Kharebava, G., Kevala, K. & Kim, H. Y. N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J. Neurochem. 125, 869–884 (2013). The first paper to demonstrate that the fatty acid ethanolamide, a derivative of DHA, is a potent neurogenic factor.
Lukiw, W. J. & Bazan, N. G. Docosahexaenoic acid and the aging brain. J. Nutr. 138, 2510–2514 (2008).
Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783 (2005). A seminal paper showing decreased unesterifed DHA and NPD1 in post-mortem samples from patients with Alzheimer's disease, suggesting that altered neuroprotective pathways may be an early event in disease pathogenesis.
Wu, A., Ying, Z. & Gomez-Pinilla, F. Dietary ω-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J. Neurotrauma 21, 1457–1467 (2004).
Rao, J. S. et al. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol. Psychiatry 12, 36–46 (2007).
Bousquet, M., Calon, F. & Cicchetti, F. Impact of ω-3 fatty acids in Parkinson's disease. Ageing Res. Rev. 10, 453–463 (2011).
Orr, S. K., Trepanier, M. O. & Bazinet, R. P. n-3 Polyunsaturated fatty acids in animal models with neuroinflammation. Prostaglandins Leukot. Essent. Fatty Acids 88, 97–103 (2013).
Bazan, N. G. et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp. Neurol. 236, 122–130 (2012).
Laye, S. Polyunsaturated fatty acids, neuroinflammation and well being. Prostaglandins Leukot Essent. Fatty Acids 82, 295–303 (2010).
Orr, S. K. & Bazinet, R. P. The emerging role of docosahexaenoic acid in neuroinflammation. Curr. Opin. Investigat. Drugs 9, 735–743 (2008).
Mingam, R. et al. Uncoupling of interleukin-6 from its signalling pathway by dietary n-3-polyunsaturated fatty acid deprivation alters sickness behaviour in mice. Eur. J. Neurosci. 28, 1877–1886 (2008).
Delpech, J. C. et al. Transgenic increase in n-3/n-6 fatty acid ratio protects against cognitive deficits induced by an immune challenge through decrease of neuroinflammation. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2014.196 (2014).
Lalancette-Hebert, M. et al. Accumulation of dietary docosahexaenoic acid in the brain attenuates acute immune response and development of postischemic neuronal damage. Stroke; J. Cerebral Circul. 42, 2903–2909 (2011).
Huang, W. L. et al. A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain: J. Neurol. 130, 3004–3019 (2007).
Minogue, A. M., Lynch, A. M., Loane, D. J., Herron, C. E. & Lynch, M. A. Modulation of amyloid-β-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid. J. Neurochem. 103, 914–926 (2007).
Song, C., Phillips, A. G., Leonard, B. E. & Horrobin, D. F. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1β in rats. Mol. Psychiatry 9, 630–638 (2004).
Lynch, A. M. et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-β challenged aged hippocampus. Neurobiol. Aging 28, 845–855 (2007).
Martin, D. S. et al. Apoptotic changes in the aged brain are triggered by interleukin-1β-induced activation of p38 and reversed by treatment with eicosapentaenoic acid. J. Biol. Chem. 277, 34239–34246 (2002).
Labrousse, V. F. et al. Short-term long chain ω3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS ONE 7, e36861 (2012).
De Smedt-Peyrusse, V. et al. Docosahexaenoic acid prevents lipopolysaccharide-induced cytokine production in microglial cells by inhibiting lipopolysaccharide receptor presentation but not its membrane subdomain localization. J. Neurochem. 105, 296–307 (2008).
Figueroa, J. D. et al. Docosahexaenoic acid pretreatment confers protection and functional improvements after acute spinal cord injury in adult rats. J. Neurotrauma 29, 551–566 (2012).
Hjorth, E. et al. ω-3 fatty acids enhance phagocytosis of Alzheimer's disease-related amyloid-β42 by human microglia and decrease inflammatory markers. J. Alzheimers Dis. 35, 697–713 (2013).
Madore, C. et al. Nutritional n-3 PUFAs deficiency during perinatal periods alters brain innate immune system and neuronal plasticity-associated genes. Brain Behav. Immun. 41, 22–31 (2014).
Hein, A. M. & O'Banion, M. K. Neuroinflammation and memory: the role of prostaglandins. Mol. Neurobiol. 40, 15–32 (2009).
Choi, S. H., Aid, S., Choi, U. & Bosetti, F. Cyclooxygenases-1 and -2 differentially modulate leukocyte recruitment into the inflamed brain. Pharmacogenom. J. 10, 448–457 (2010).
Choi, S. H., Langenbach, R. & Bosetti, F. Cyclooxygenase-1 and -2 enzymes differentially regulate the brain upstream NF-κ B pathway and downstream enzymes involved in prostaglandin biosynthesis. J. Neurochem. 98, 801–811 (2006).
Aid, S., Langenbach, R. & Bosetti, F. Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J. Neuroinflamm. 5, 17 (2008).
Samuelsson, B., Dahlen, S. E., Lindgren, J. A., Rouzer, C. A. & Serhan, C. N. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237, 1171–1176 (1987).
Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).
Hjorth, E. & Freund-Levi, Y. Immunomodulation of microglia by docosahexaenoic acid and eicosapentaenoic acid. Curr. Opin. Clin. Nutr. Metabol. Care 15, 134–143 (2012).
Lukiw, W. J. & Bazan, N. G. Inflammatory, apoptotic, and survival gene signaling in Alzheimer's disease. A review on the bioactivity of neuroprotectin D1 and apoptosis. Mol. Neurobiol. 42, 10–16 (2010).
Pifferi, F. et al. (n-3) polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats. J. Nutr. 135, 2241–2246 (2005).
Pifferi, F. et al. n-3 Fatty acids modulate brain glucose transport in endothelial cells of the blood-brain barrier. Prostaglandins Leukotrienes, Essent. Fatty Acids 77, 279–286 (2007).
Green, J. T., Liu, Z. & Bazinet, R. P. Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet. J. Lipid Res. 51, 535–543 (2010).
Igarashi, M., Kim, H. W., Chang, L., Ma, K. & Rapoport, S. I. Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J. Neurochem. 120, 985–997 (2012).
Rao, J. S. et al. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol. Psychiatry 12, 151–157 (2007).
DeMar, J. C. Jr, Ma, K., Bell, J. M. & Rapoport, S. I. Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. J. Neurochem. 91, 1125–1137 (2004).
Stark, K. D., Lim, S. Y. & Salem, N. Jr. Artificial rearing with docosahexaenoic acid and n-6 docosapentaenoic acid alters rat tissue fatty acid composition. J. Lipid Res. 48, 2471–2477 (2007).
Lim, S. Y., Hoshiba, J. & Salem, N. Jr. 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 (2005).
Cunnane, S. C. et al. Fish, docosahexaenoic acid and Alzheimer's disease. Progress Lipid Res. 48, 239–256 (2009).
McNamara, R. K. et al. Selective deficits in the ω-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol. Psychiatry 62, 17–24 (2007).
McNamara, R. K. et al. Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder. Psychiatry Res. 160, 285–299 (2008).
Di Paolo, G. & Kim, T. W. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nature Rev. Neurosci. 12, 284–296 (2011).
Lin, P. Y., Huang, S. Y. & Su, K. P. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol. Psychiatry 68, 140–147 (2010).
McNamara, R. K. et al. Lower docosahexaenoic acid concentrations in the postmortem prefrontal cortex of adult depressed suicide victims compared with controls without cardiovascular disease. J. Psychiatr. Res. 47, 1187–1191 (2013).
Igarashi, M. et al. Brain lipid concentrations in bipolar disorder. J. Psychiatr. Res. 44, 177–182 (2010).
McNamara, R. K. Long-chain ω-3 fatty acid deficiency in mood disorders: rationale for treatment and prevention. Curr. Drug Discov. Technol. 10, 233–244 (2013).
Su, K. P. et al. Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-α-induced depression by regulating polyunsaturated fatty acids levels. Biol. Psychiatry 67, 550–557 (2010).
Appleton, K. M., Rogers, P. J. & Ness, A. R. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am. J. Clin. Nutr. 91, 757–770 (2010).
Sublette, M. E., Ellis, S. P., Geant, A. L. & Mann, J. J. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 72, 1577–1584 (2011).
Lin, P. Y. & Su, K. P. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of ω-3 fatty acids. J. Clin. Psychiatry 68, 1056–1061 (2007).
Martins, J. G. EPA but not DHA appears to be responsible for the efficacy of ω-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J. Am. College Nutr. 28, 525–542 (2009).
Bloch, M. H. & Hannestad, J. ω-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol. Psychiatry 17, 1272–1282 (2012).
DeMar, J. C. Jr et al. One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J. Lipid Res. 47, 172–180 (2006).
Chalon, S. ω-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent. Fatty Acids 75, 259–269 (2006).
de la Presa Owens, S. & Innis, S. M. Docosahexaenoic and arachidonic acid prevent a decrease in dopaminergic and serotoninergic neurotransmitters in frontal cortex caused by a linoleic and α-linolenic acid deficient diet in formula-fed piglets. J. Nutr. 129, 2088–2093 (1999).
Kodas, E. et al. Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat. J. Neurochem. 89, 695–702 (2004).
Bondi, C. O. et al. Adolescent behavior and dopamine availability are uniquely sensitive to dietary ω-3 fatty acid deficiency. Biol. Psychiatry 75, 38–46 (2013).
Mocking, R. J. et al. Relationship between the hypothalamic-pituitary-adrenal-axis and fatty acid metabolism in recurrent depression. Psychoneuroendocrinology 38, 1607–1617 (2013).
Kiecolt-Glaser, J. K., Belury, M. A., Andridge, R., Malarkey, W. B. & Glaser, R. ω-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav. Immun. 25, 1725–1734 (2011).
Delarue, J. et al. Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab. 29, 289–295 (2003).
Michaeli, B., Berger, M. M., Revelly, J. P., Tappy, L. & Chiolero, R. Effects of fish oil on the neuro-endocrine responses to an endotoxin challenge in healthy volunteers. Clin. Nutr. 26, 70–77 (2007).
Levant, B. et al. Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: Interactions with reproductive status in female rats. Psychoneuroendocrinology 33, 1279–1292 (2008).
Ferraz, A. C. et al. Chronic ω-3 fatty acids supplementation promotes beneficial effects on anxiety, cognitive and depressive-like behaviors in rats subjected to a restraint stress protocol. Behav. Brain Res. 219, 116–122 (2011).
Larrieu, T. et al. Hypothalamo-pituitary-adrenal axis mediates n-3 polyunsaturated fatty acids deficient-diet induced depressive- and anxiety-like symptoms along with neuronal atrophy. Transl. Psychiatry 4, e437 (2014).
Song, C., Zhang, X. Y. & Manku, M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: effects of chronic ethyl-eicosapentaenoate treatment. J. Neurosci. 29, 14–22 (2009).
Joffre, C., Nadjar, A., Lebbadi, M., Calon, F. & Laye, S. n-3 LCPUFA improves cognition: The young, the old and the sick. Prostaglandins Leukot Essent. Fatty Acids 91, 1–20 (2014).
Ramakrishnan, U., Imhoff-Kunsch, B. & DiGirolamo, A. M. Role of docosahexaenoic acid in maternal and child mental health. Am. J. Clin. Nutr. 89, 958S–962S (2009).
Young, G. S., Maharaj, N. J. & Conquer, J. A. Blood phospholipid fatty acid analysis of adults with and without attention deficit/hyperactivity disorder. Lipids 39, 117–123 (2004).
Frensham, L. J., Bryan, J. & Parletta, N. Influences of micronutrient and ω-3 fatty acid supplementation on cognition, learning, and behavior: methodological considerations and implications for children and adolescents in developed societies. Nutr. Rev. 70, 594–610 (2012).
Montgomery, P., Burton, J. R., Sewell, R. P., Spreckelsen, T. F. & Richardson, A. J. Low blood long chain ω-3 fatty acids in UK children are associated with poor cognitive performance and behavior: a cross-sectional analysis from the DOLAB study. PloS one 8, e66697 (2013).
Kuratko, C. N., Barrett, E. C., Nelson, E. B. & Salem, N. Jr. The relationship of docosahexaenoic acid (DHA) with learning and behavior in healthy children: a review. Nutrients 5, 2777–2810 (2013).
Moranis, A. et al. Long term adequate n-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice. Brain Behav. Immun. 26, 721–731 (2012).
Fedorova, I. et al. An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze. Prostaglandins Leukot Essent. Fatty Acids 77, 269–277 (2007).
Connor, S., Tenorio, G., Clandinin, M. T. & Sauve, Y. DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus. Appl. Physiol. Nutr. Metab. 37, 880–887 (2012).
Kavraal, S. et al. Maternal intake of ω-3 essential fatty acids improves long term potentiation in the dentate gyrus and Morris water maze performance in rats. Brain Res. 1482, 32–39 (2012).
Cunnane, S. C., Chouinard-Watkins, R., Castellano, C. A. & Barberger-Gateau, P. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence? Prostaglandins Leukot Essent. Fatty Acids 88, 61–70 (2013).
Igarashi, M. et al. Disturbed choline plasmalogen and phospholipid fatty acid concentrations in Alzheimer's disease prefrontal cortex. J. Alz. Dis. 24, 507–517 (2011).
Samieri, C. et al. ω-3 fatty acids and cognitive decline: modulation by ApoEepsilon4 allele and depression. Neurobiol. Aging 32, 2317.e13-22 (2011).
Tan, Z. S. et al. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology 78, 658–664 (2012).
Samieri, C. et al. Plasma long-chain ω-3 fatty acids and atrophy of the medial temporal lobe. Neurology 79, 642–650 (2012).
Ronnemaa, E. et al. Serum fatty-acid composition and the risk of Alzheimer's disease: a longitudinal population-based study. Eur. J. Clin. Nutr. 66, 885–890 (2012).
Quinn, J. F. et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 304, 1903–1911 (2010).
Feart, C. et al. 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 (2008).
Mazereeuw, G., Lanctot, K. L., Chau, S. A., Swardfager, W. & Herrmann, N. Effects of ω-3 fatty acids on cognitive performance: a meta-analysis. Neurobiol. Aging 33, e17–29 (2012).
Freund-Levi, Y. et al. ω-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: ωD study: a randomized double-blind trial. Arch. Neurol. 63, 1402–1408 (2006).
Huang, T. L. et al. Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology 65, 1409–1414 (2005).
Plourde, M. et al. Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-α L162V polymorphism in men. Br. J. Nutr. 102, 1121–1124 (2009).
Vandal, M. et al. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J. Neurochem. 129, 516–526 (2014). This paper connects the Alzheimer's risk factor APOE4 to decreased uptake of DHA in the brain.
Lim, G. P. et al. A diet enriched with the ω-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J. Neurosci. 25, 3032–3040 (2005).
Green, K. N. et al. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-β and tau pathology via a mechanism involving presenilin 1 levels. J. Neurosci. 27, 4385–4395 (2007).
Zhao, Y. et al. Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARgamma-mediated mechanisms in Alzheimer's disease models. PloS one 6, e15816 (2011).
Calon, F. & Cole, G. Neuroprotective action of ω-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot. Essent. Fatty Acids 77, 287–293 (2007).
Frautschy, S. A. & Cole, G. M. What was lost in translation in the DHA trial is whom you should intend to treat. Alzheimer Res. Ther. 3, 2 (2011).
Evans, D. R. et al. Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment. Prostaglandins Leukot Essent. Fatty Acids 69, 393–399 (2003).
Sethom, M. M. et al. Polyunsaturated fatty acids deficits are associated with psychotic state and negative symptoms in patients with schizophrenia. Prostaglandins Leukot Essent. Fatty Acids 83, 131–136 (2010).
Hamazaki, K., Hamazaki, T. & Inadera, H. Abnormalities in the fatty acid composition of the postmortem entorhinal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. Psychiatry Res. 210, 346–350 (2013).
Taha, A. Y., Cheon, Y., Ma, K., Rapoport, S. I. & Rao, J. S. Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. J. Psychiatr. Res. 47, 636–643 (2013).
McNamara, R. K. et al. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications. Schizophr. Res. 91, 37–50 (2007).
Liu, Y., Jandacek, R., Rider, T., Tso, P. & McNamara, R. K. Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition. Schizophr. Res. 109, 113–120 (2009).
Watanabe, A. et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5, e297 (2007).
Amminger, G. P. et al. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch. Gen. Psychiatry 67, 146–154 (2010).
Wymann, M. P. & Schneiter, R. Lipid signalling in disease. Nature Rev. Mol. Cell Biol. 9, 162–176 (2008).
Nery, F. G. et al. Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum. Psychopharmacol. 23, 87–94 (2008).
Kim, H. W., Rapoport, S. I. & Rao, J. S. Altered arachidonic acid cascade enzymes in postmortem brain from bipolar disorder patients. Mol. Psychiatry 16, 419–428 (2011).
Kushner, S. F., Khan, A., Lane, R. & Olson, W. H. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 8, 15–27 (2006).
Musto, A. E., Gjorstrup, P. & Bazan, N. G. The ω-3 fatty acid-derived neuroprotectin D1 limits hippocampal hyperexcitability and seizure susceptibility in kindling epileptogenesis. Epilepsia 52, 1601–1608 (2011).
Taha, A. Y. et al. A minimum of 3 months of dietary fish oil supplementation is required to raise amygdaloid afterdischarge seizure thresholds in rats—implications for treating complex partial seizures. Epilepsy Behav. 27, 49–58 (2013).
Trepanier, M. O. et al. Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses. Epilepsy Res. 99, 225–232 (2012).
Chauveau, F. et al. Brain-targeting form of docosahexaenoic acid for experimental stroke treatment: MRI evaluation and anti-oxidant impact. Curr. Neurovascular Res. 8, 95–102 (2011). A novel example of how to target the brain with DHA in brain injury.
King, V. R. et al. ω-3 fatty acids improve recovery, whereas ω-6 fatty acids worsen outcome, after spinal cord injury in the adult rat. J. Neurosci. 26, 4672–4680 (2006).
Picq, M. et al. DHA metabolism: targeting the brain and lipoxygenation. Mol. Neurobiol. 42, 48–51 (2010).
Fischer, R. et al. Dietary ω-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway. J. Lipid Res. 55, 1150–1164 (2014).
Topol, E. J. et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet 376, 517–523 (2010).
Cunnane, S. C., Francescutti, V., Brenna, J. T. & Crawford, M. A. Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate. Lipids 35, 105–111 (2000).
Holman, R. T., Johnson, S. B. & Hatch, T. F. A case of human linolenic acid deficiency involving neurological abnormalities. Am. J. Clin. Nutr. 35, 617–623 (1982).
Scott, B. L. & Bazan, N. G. Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc. Natl Acad. Sci. USA 86, 2903–2907 (1989).
Domenichiello, A. F., Chen, C. T., Trepanier, M. O., Stavro, P. M. & Bazinet, R. P. Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats. J. Lipid Res. 55, 62–74 (2014).
McCloy, U., Ryan, M. A., Pencharz, P. B., Ross, R. J. & Cunnane, S. C. A comparison of the metabolism of eighteen-carbon 13C-unsaturated fatty acids in healthy women. J. Lipid Res. 45, 474–485 (2004).
Lefkowitz, W., Lim, S. Y., Lin, Y. & Salem, N. Jr. Where does the developing brain obtain its docosahexaenoic acid? Relative contributions of dietary α-linolenic acid, docosahexaenoic acid, and body stores in the developing rat. Pediatr. Res. 57, 157–165 (2005).
Greiner, R. C., Winter, J., Nathanielsz, P. W. & Brenna, J. T. Brain docosahexaenoate accretion in fetal baboons: bioequivalence of dietary α-linolenic and docosahexaenoic acids. Pediatr. Res. 42, 826–834 (1997).
Barden, A., Mas, E., Croft, K. D., Phillips, M. & Mori, T. A. Short-term n-3 fatty acid supplementation but not aspirin increases plasma proresolving mediators of inflammation. J. Lipid. Res. 55, 2401–2407 (2014).
The authors apologize to those whose valuable work was not cited owing to space limitations. R.P.B. acknowledges funding from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and holds a Canada Research Chair in Brain Lipid Metabolism. S.L. is supported by Institut National de la Recherche Agronomique (INRA), Bordeaux University, Région Aquitaine and Agence Nationale de la Recherche (ANR).
R.P.B. has received grants from Bunge Ltd and the International Life Sciences Institute for studies related to fatty acids and the brain.
Sensations of tingling, tickling, prickling or burning of a person's skin.
- Lands cycle
The process of deacylation and reacylation of fatty acids, sometimes referred to as recycling within membrane phospholipids. The pathway was discovered by William Lands.
Derivatives of a fatty acid that are bioactive. The term lipid mediator is distinct from derivative as it implies that the molecule is bioactive.
- Specialized pro-resolving mediators
Mediators that promote pro-resolution, which is an active process involving several lipids that turns off pro-inflammatory signalling and promotes the clearance of leukocytes and cellular debris, thereby returning the tissue to homeostasis.
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Bazinet, R., Layé, S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 15, 771–785 (2014). https://doi.org/10.1038/nrn3820
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