Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the brain where it serves to regulate several important processes and, in addition, serves as a precursor to bioactive mediators. Given that the capacity of the brain to synthesize DHA locally is appreciably low, the uptake of DHA from circulating lipid pools is essential to maintaining homeostatic levels. Although, several plasma pools have been proposed to supply the brain with DHA, recent evidence suggests non-esterified-DHA and lysophosphatidylcholine-DHA are the primary sources. The uptake of DHA into the brain appears to be regulated by a number of complementary pathways associated with the activation and metabolism of DHA, and may provide mechanisms for enrichment of DHA within the brain. Following entry into the brain, DHA is esterified into and recycled amongst membrane phospholipids contributing the distribution of DHA in brain phospholipids. During neurotransmission and following brain injury, DHA is released from membrane phospholipids and converted to bioactive mediators which regulate signaling pathways important to synaptogenesis, cell survival, and neuroinflammation, and may be relevant to treating neurological diseases. In the present review, we provide a comprehensive overview of brain DHA metabolism, encompassing many of the pathways and key enzymatic regulators governing brain DHA uptake and metabolism. In addition, we focus on the release of non-esterified DHA and subsequent production of bioactive mediators and the evidence of their proposed activity within the brain. We also provide a brief review of the evidence from post-mortem brain analyses investigating DHA levels in the context of neurological disease and mood disorder, highlighting the current disparities within the field.

Carrying the apoE e4 allele (E4þ ) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E42 ), E4þ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4þ. The aim of the present study was to evaluate [ 13 C]DHA metabolism over 28 d in E4þ v. E42. A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [ 13 C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4þ and thirty-four were E42. In E4þ, mean plasma [ 13 C]DHA was 31 % lower than that in E42, and cumulative b-oxidation of [ 13 C]DHA was higher than that in E42 1-28 d post-dose (P#0·05). A genotype £ time interaction was detected for cumulative b-oxidation of [ 13 C]DHA (P#0·01). The whole-body half-life of [ 13 C]DHA was 77 % lower in E4þ compared with E42 (P#0·01). In E4þ and E42, the percentage dose of [ 13 C]DHA recovered/h as 13 CO 2 correlated with [ 13 C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4þ compared with E42 (P# 0·05). These results indicate that DHA metabolism is disturbed in E4þ, and may help explain why there is no association between DHA levels in plasma and cognition in E4þ. However, whether E4þ disturbs the metabolism of 13 C-labelled fatty acids other than DHA cannot be deduced from the present study.

BackgroundHigher fish or higher docosahexaenoic acid (DHA) intake normally correlates positively with higher plasma DHA level, but recent evidence suggests that the positive relationship between intake and plasma levels of DHA is less clear in the elderly.MethodsWe compared the metabolism of 13C-DHA in six healthy elderly (mean - 77 y old) and six young adults (mean - 27 y old). All participants were given a single oral dose of 50 mg of uniformly labelled 13C-DHA. Tracer incorporation into fatty acids of plasma triglycerides, free fatty acids, cholesteryl esters and phospholipids, as well as apparent retroconversion and β-oxidation of 13C-DHA were evaluated 4 h, 24 h, 7d and 28d later.ResultsPlasma incorporation and β-oxidation of 13C-DHA reached a maximum within 4 h in both groups, but 13C-DHA was transiently higher in all plasma lipids of the elderly 4 h to 28d later. At 4 h post-dose, 13C-DHA β-oxidation was 1.9 times higher in the elderly, but over 7d, cumulative β-oxidation of 13C-DHA was not different in the two groups (35% in the elderly and 38% in the young). Apparent retroconversion of 13C-DHA was well below 10% of 13C-DHA recovered in plasma at all time points, and was 2.1 times higher in the elderly 24 h and 7d after tracer intake.ConclusionsWe conclude that 13C-DHA metabolism changes significantly during healthy aging. Since DHA is a potentially important molecule in neuro-protection, these changes may be relevant to the higher vulnerability of the elderly to cognitive decline.

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