Role of Omega-3 Fatty Acids in the Brain and Neurological Diseases

Fatty Acid Types

The fat found in foods consists mostly of a heterogeneous mixture of triacylglycerols (triglycerides)—glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties:

  1. saturated fatty acids, which are usually solid at room temperature
  2. unsaturated fatty acids, which are liquid at room temperature.

The term "saturation" refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach.1

Unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram).

The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed, and many other vegetable oils) contain more than one double bond.

Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds).

PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1.1

*IUPAC = International Union of Pure and Applied Chemistry

Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n-6 shorter-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called very-longchain PUFAs (VLCPUFAs).

Fatty Acid Metabolism

Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the shorter-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered "essential" for humans, because they can all be synthesized from the shorter chain fatty acids.

Following ingestion, ALA and LA can be converted in the liver to the long chain, moreunsaturated n-3 and n-6 VLCPUFAs by a complex set of synthetic pathways that share several enzymes. VLC PUFAs retain the original sites of desaturation (including n-3 or n-6). The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longerchain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below).

The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further elongated, desaturated, and beta-oxidized to produce docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and docosanoids, respectively, are known to play several other critical roles, some of which are discussed further below. The conversion from parent fatty acids into the VLC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways.

Physiological Functions of EPA and AA

As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain. Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone-like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulatory molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally – in the cells that synthesize them or adjacent cells.

Processes affected include:

  • movement of calcium and other substances into and out of cells
  • relaxation and contraction of muscles
  • inhibition and promotion of clotting
  • regulation of secretions including digestive juices and hormones
  • control of fertility, cell division, and growth

The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. The long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins.2

Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma. EPA (0522:6 n-3) also affects lipoprotein metabolism and decreases the production of substances – including cytokines, interleukin 1Β (IL-1Β), and tumor necrosis factor a (TNF-Α) – that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]). DPA (22:5n-3), the elongation product of EPA, is metabolized to DHA (22:6n-3). DHA (22:6n-3) is the precursor to a newly-described metabolite called 10,17S-docosatriene, which is part of a family of compounds called "resolvins". They are in the brain in response to an ischemic insult and counteract the pro-inflammatory actions of infiltrating leukocytes by blocking interleukin 1-beta-induced NF-kappaB activation and cyclooxygenase-2 expression. DHA also plays a role in retinal rod outer segments by influencing membrane fluidity so as to optimize G protein coupled signaling.7 The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs and VLCPUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega-6 fatty acids compete for common enzymes in the fatty acid metabolic pathway, including delta-6 desaturase, as well as the rate-limiting enzymes in the eicosanoid pathway – phospholipases A2, cyclooxygenase, and lipoxygenase. DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in human breast milk but not in formula).

Dietary Sources and Requirements

Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables. Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils.

The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89 percent of the total PUFAs consumed, and ALA accounts for 9 percent. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids.

* - Dietary supplement
** - Also called rapeseed oil
◊ -The amounts of ALA, EPA, and DHA in human milk vary greatly as a function of maternal diet; the amount of DHA rarely seems to exceed 25 percent of the total n-3 PUFA content (ALA is present in the greatest amount), but that content as well as the proportion of DHA is assumed to meet the requirements of the infant.

Physiological Role of Omega-3 Fatty Acids in the Brain

About 50 to 60 percent of the dry weight portion of the human brain consists of lipids. PUFAs constitute approximately 35% of that lipid content. Omega -3 fatty acids, particularly EPA and DHA, play important roles in the development and maintenance of normal central nervous system (CNS) structure and function. Along with the omega-6 fatty acid, AA, DHA is a major constituent of neuronal membranes, making up about 20 percent of the brain's dry weight. Synapses contain a high concentration of DHA, which appears to play a role in synaptic signal transduction.

DHA is also important for normal cognitive development. In addition, the anti-inflammatory compounds for which DHA is a precursor may function in the brain to protect against ischemic damage. PUFAs in general play important roles in structural and functional maintenance of neuronal membranes, neurotransmission, and eicosanoid biosynthesis, as well as in the maintenance of membrane fluidity and flexibility and in the modulation of ion channels, receptors, and ATPases.5

The importance of PUFAs in maintenance of adequate membrane rigidity is evidenced by the loss of fluidity that follows decreased in PUFAs, leading to changes in the orientation and function of receptors and ion channels, such as calcium and sodium channels.

Work in animal models has reported superior learning and memory in animals fed omega-3 fatty acids compared with control animals. In mouse models, dietary DHA improved memory, increased synapse density and decreased amyloid beta toxicity, thus providing evidence of protection against AD and cognitive decline.3

Omega-3 Fatty Acids in Neurologic Disorders

Deficiencies in omega-3 FA and/or an imbalance in the ratio of omega-6 FA to omega-3 FA have been implicated in a variety of disorders affecting the CNS, including Alzheimer's disease (AD), several psychiatric disorders, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, ischemic brain injury, and multiple sclerosis (MS).

In several studies, fish (total omega-3 fatty acid consumption) was associated with a reduced risk as well as significant reduction in the incidence of Alzheimer's disease.

Also, consumption of fish once a week throughout pregnancy was associated with a lower risk of cerebral palsy compared with no fish intake.

Indeed, dietary intake of omega-3 FA has been associated with a reduced incidence of MS since 1950s. Various animal and human studies have suggested several possible biological mechanisms for the role of FA in disease processes. Evidence for a positive association between intake of omega-3 FA and reduction of cardiovascular risk and adverse outcomes, along with the finding that certain forms of dementia have been related to cardiovascular risk factors, suggest that one mechanism linking FA and cognitive function or dementia may be atherosclerosis and thrombotic events. Inflammation is another mechanism that may explain the role that omega-3 fatty acids play in dementia.

Several intervention trials in human infants have investigated the effects of omega-3 FA on cognitive development. Research has also shown these FA to be important in human infant visual development. A meta-analysis of several intervention trials showed that healthy pre-term infants who were administered DHA-supplemented formula had significantly higher visual resolution acuity at two and four months of age compared with infants fed DHA-free formula. However, few clinical intervention trials have examined the role of omega-3 FA in changes in cognitive function with aging and adult neurological conditions. The studies that have investigated the relationship between omega-3 FA intake and cognitive function, dementia, or other neurological diseases are mainly observational.2


References

  1. Effects of Omega-3 Fatty Acids on Cancer
  2. Effects of Omega-3 Fatty Acids on Cognitive Function with Aging, Dementia, and Neurological Diseases
  3. The Effi cacy of Omega–3 Fatty Acids on Cognitive Function in Aging and Dementia: A Systematic Review
  4. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association
  5. Research Mounts on Benefits of Omega-3s