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Polyunsaturated fatty acids and their metabolites in brain function and disease

Key Points

  • 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.

Abstract

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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Figure 1: Synthesis of PUFAs in the liver.
Figure 2: Fatty acid entry from the plasma into the brain.
Figure 3: Fatty acid release and conversion to mediators upon receptor-mediated signal transduction.
Figure 4: Dietary PUFAs influence endocannabinoid-mediated synaptic plasticity.
Figure 5: Roles of PUFAs in the brain.

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Acknowledgements

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).

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R.P.B. has received grants from Bunge Ltd and the International Life Sciences Institute for studies related to fatty acids and the brain.

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Glossary

Accretion

Gradual accumulation.

Paresthesias

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.

Mediators

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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