The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer's disease

Among omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA, 22:6n-3) is important for adequate brain development and cognition. DHA is highly concentrated in the brain and plays an essential role in brain functioning. DHA, one of the major constituents in fish fats, readily crosses the blood–brain barrier from blood to the brain. Its critical role was further supported by its reduced levels in the brain of Alzheimer's disease (AD) patients. This agrees with a potential role of DHA in memory, learning and cognitive processes. Since there is yet no cure for dementia such as AD, there is growing interest in the role of DHA-supplemented diet in the prevention of AD pathogenesis. Accordingly, animal, epidemiological, preclinical and clinical studies indicated that DHA has neuroprotective effects in a number of neurodegenerative conditions including AD. The beneficial effects of this key omega-3 fatty acid supplementation may depend on the stage of disease progression, other dietary mediators and the apolipoprotein ApoE genotype. Herein, our review investigates, from animal and cell culture studies, the molecular mechanisms involved in the neuroprotective potential of DHA with emphasis on AD.     

Docosahexaenoic acid homeostasis,brain aging and Alzheimer's disease: Can we reconcile the evidence?

A crossroads has been reached on research into docosahexaenoic acid (DHA) and Alzheimer's disease (AD). On the one hand, several prospective observational studies now clearly indicate a protective effect of higher fish and DHA intake against risk of AD. On the other hand, once AD is clinically evident, supplementation trials demonstrate essentially no benefit of DHA in AD. Despite apparently low DHA intake in AD, brain DHA levels are frequently the same as in controls, suggesting that low DHA intake results in low plasma DHA but does not necessarily reduce brain DHA in humans. Animal models involving dietary omega-3 fatty acid deficiency to deplete brain DHA may therefore not be appropriate in AD research. Studies in the healthy elderly suggest that DHA homeostasis changes during aging. Tracer methodology now permits estimation of DHA half-life in the human brain and whole body. Apolipoprotein E alleles have an important impact not only on AD but also on DHA homeostasis in humans. We therefore encourage further development of innovative approaches to the study of DHA metabolism and its role in human brain function. A better understanding of DHA metabolism in humans will hopefully help explain how higher habitual DHA intake protects against the risk of deteriorating cognition during aging and may eventually give rise to a breakthrough in the treatment of AD.     

Omega-3 fatty acids and dementia

More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid β peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Aβ, including two major kinases that phosphorylate the microtubule-associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline—with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants.     

Omega-3 fatty acids and neuropsychiatric disorders

Epidemiological evidence suggests that dietary consumption of the long chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish or fish oil, may modify the risk for certain neuropsychiatric disorders. As evidence, decreased blood levels of omega-3 fatty acids have been associated with several neuropsychiatric conditions, including Attention Deficit (Hyperactivity) Disorder, Alzheimer's Disease, Schizophrenia and Depression. Supplementation studies, using individual or combination omega-3 fatty acids, suggest the possibility for decreased symptoms associated with some of these conditions. Thus far, however, the benefits of supplementation, in terms of decreasing disease risk and/or aiding in symptom management, are not clear and more research is needed. The reasons for blood fatty acid alterations in these disorders are not known, nor are the potential mechanisms by which omega-3 fatty acids may function in normal neuronal activity and neuropsychiatric disease prevention and/or treatment. It is clear, however, that DHA is the predominant n-3 fatty acid found in the brain and that EPA plays an important role as an anti-inflammatory precursor. Both DHA and EPA can be linked with many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and enzyme regulation and gene expression. This review summarizes the knowledge in terms of dietary omega-3 fatty acid intake and metabolism, as well as evidence pointing to potential mechanisms of omega-3 fatty acids in normal brain functioning, development of neuropsychiatric disorders and efficacy of omega-3 fatty acid supplementation in terms of symptom management.     

The effects of a diet rich in docosahexaenoic acid on organ and vascular fatty acid composition in spontaneously hypertensive rats

Previous research has shown that dietary docosahexaenoic acid (DHA) attenuates the development of high blood pressure in young spontaneously hypertensive rats (SHR). The purpose of this study was to investigate the effects of dietary DHA on organ and vascular fatty acid composition in SHR. Given the important structural and functional role of fatty acids in cell membranes, alterations in fatty acid composition may contribute to the antihypertensive effect of DHA. SHR were fed a purified diet containing either a corn/soybean oil mixture (CSO, control) or a DHA-enriched oil for 6 weeks. The DHA diet markedly increased the levels of DHA in the aorta, renal artery, plasma, liver, heart, kidney, and lung by 5-, 15-, 7-, 6-, 3.8-, 3.5-, and 8.8-fold (P<0.001), respectively. The levels of eicosapentaenoic acid were also increased while there was a concomitant reduction in arachidonic and adrenic acids. Therefore, dietary DHA increases the incorporation of omega-3 polyunsaturated fatty acids in specific organs and vascular tissue in SHR at the expense of omega-6 polyunsaturated fatty acids.     

Evolutionary Aspects of Diet: The Omega-6/Omega-3 Ratio and the Brain

Several sources of information suggest that human beings evolved on a diet that had a ratio of omega-6 to omega-3 fatty acids (FA) of about 1/1; whereas today, Western diets have a ratio of 10/1 to 20–25/1, indicating that Western diets are deficient in omega-3 FA compared with the diet on which humans evolved and their genetic patterns were established. Omega-6 and omega-3 FA are not interconvertible in the human body and are important components of practically all cell membranes. Studies with nonhuman primates and human newborns indicate that docosahexaenoic acid (DHA) is essential for the normal functional development of the brain and retina, particularly in premature infants. DHA accounts for 40% of the membrane phospholipid FA in the brain. Both eicosapentaenoic acid (EPA) and DHA have an effect on membrane receptor function and even neurotransmitter generation and metabolism. There is growing evidence that EPA and DHA could play a role in hostility and violence in addition to the beneficial effects in substance abuse disorders and alcoholism. The balance of omega-6 and omega-3 FA is important for homeostasis and normal development throughout the life cycle.     

Fatty acid correlates of temperament in adolescent boys with attention deficit hyperactivity disorder

Atypical fatty acid metabolism has been reported in attention deficit hyperactivity disorder (ADHD), however, its relationship with temperament in this population is unclear. The current study investigated the association between blood levels of fatty acids implicated in brain structure and function (omega-3, omega-6, omega-9) and personality traits of stability (neuroticism, conscientiousness and agreeableness) and plasticity (extraversion and openness). Twenty right-handed adolescent boys with ADHD completed a self-report NEO-FFI personality questionnaire, and had fatty acid content assessed from red blood using gas chromatography. Pearson's correlations showed no significant associations between omega-3 levels and personality. After correction for multiple comparisons, Adrenic Acid (C22:4n6) was inversely associated with stability. Oleic acid (C18:1n9) was positively associated with plasticity. Results are in line with a role of fatty acids in brain function. They suggest that those fatty acids that are involved in myelination (Adrenic, Oleic) have the strongest associations with temperament in adolescents with ADHD.     

Biomarkers of DHA status

Docosahexaenoic acid (DHA, 22:6n-3) is a long chain omega-3 fatty acid that is the primary n-3 fatty acid found in the central nervous system where it plays both a structural and functional role in cells. Because the tissues of interest are generally inaccessible for fatty acid analysis in humans and because precise DHA intake is difficult to determine, surrogate biomarkers are important for defining DHA status. Analysis of total lipid extracts or phospholipids from plasma or erythrocytes by gas chromatography meet the criteria for a useful biomarker of DHA status. Furthermore, both plasma and erythrocyte DHA levels have been correlated with brain, cardiac, and other tissue levels. Use of these biomarkers of DHA status will enable future clinical trials and observational studies to define more precisely the DHA levels required for either disease prevention or other functional benefits.     

Regulation of intracellular lipid metabolism by the preparation of omega-3 phospholipids from marine organisms in deficiency of essential fatty acids in rats

It has been established that a deficit of essential fatty acids (EFA) in the animal organism induces specific modifications of composition of fatty acid (FA) of general phospholipids and plasmalogenic P1 in microsomal tissue membranes with various functions and affects the activity of phospholipase A2. It has been shown that arachidonic (AA), docosapentaenoic (DPA) and docosahexaenoic (DHA) acids in the composition of general phospholipids - phosphatidylcholine (PC), phosphatidylethanolamine (PEA) and plasmalogens PC and PEA react to EFA deficit in the organism. Quantitative redistribution of AA, DPA, DHA of FA in general phospholipids and plasmalogenic microsomal membranes depending on their functions was found under EFA deficit in the organism. Deficit of DHA and plasmalogenic phospholipids evidences that the status of cell plasmalogens affects the level of PUFA at EFA deficit in the organism. AA and DHA can be a selective target for plasmalogens. The drug of omega-3 phospholipids, considerable amount of DHA and eicosapentaenoic (EPA)FA being present in their structure, increases the amount of plasmalogens and decreases the amount of AA in the brain, heart and reproductive organs. It was also found that EFA deficit in the organism favours the increase of lisoPEA, lisoPC, free FA (FFA) connected with the increase of activity of endogenic phospholippase A2 and plasmalogen-selective phospholipase A2. The omega-3 phospholipase from marine organisms at EFA defecit decreases the amount of FFA, lisophospholipids and activity of phospholipase A2 in the microsomas of the studied tissues. The drug of omega-3 phospholipids normalizes the state and functions of the brain, liver, and heart tissues, reproductive organs against a background of EFA defecit and regulates the synthesis of biologocically active metabolites of AA in the organism.     

Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats

Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B(12) are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B(12) deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B(12) deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B(12) lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta.     

Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: A review of randomized controlled trials

The question of whether a dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (ARA) imparts advantages to visual or cognitive development in term infants has been debated for many years. DHA and ARA are present in human milk, and nursing infants consume these fatty acids needed for rapid synthesis of cell membranes, particularly neural cells. The reported mean DHA and ARA levels of human milk worldwide are 0.32% and 0.47% of total fatty acids, respectively. Prior to 2002 in the US, formula-fed infants did not receive these fatty acids and relied solely on endogenous conversion of the dietary essential omega-3 (n-3) and omega-6 (n-6) fatty acids, α-linolenic and linoleic acids, to DHA and ARA, respectively. Formula-fed infants were found to have significantly less accretion of DHA in brain cortex after death than breastfed infants. Numerous studies have found positive correlations between blood DHA levels and improvements in cognitive or visual function outcomes of breastfed and formula-fed infants. Results of randomized controlled clinical trials of term formula-fed infants evaluating functional benefits of dietary DHA and ARA have been mixed, likely due to study design heterogeneity. A comparison of visual and cognitive outcomes in these trials suggests that dietary DHA level is particularly relevant. Trials with formulas providing close to the worldwide human milk mean of 0.32% DHA were more likely to yield functional benefits attributable to DHA. We agree with several expert groups in recommending that infants receive at least 0.3% DHA, with at least 0.3% ARA, in infant feedings; in addition, some clinical evidence suggests that an ARA:DHA ratio greater than 1:1 is associated with improved cognitive outcomes.     

Effect of phospholipids containing omega-3 fatty acids on structural changes of microsomal lipids in cell membranes of functionally different cells

As a result of the experimental researches conducted it has been shown that administration of some normal animal marine phospholipids (PL) including in their structure omega-3 polyunsaturated fatty acids (PUFA) provides for quantitative changes of individual PL, fatty acids (FA) content and quantity in general and individual PL of liver, heart, brain and gonads microsomes. While estimating general microsomal PL fraction FA content under the action of PL omega-3 PUFA FA concentration change, unsaturation index (omega 6/omega 3) and relation of arachidonic acid to docosahexenic (AA/DHA) decrease have been identified. The decrease of AA/DHA relationship occurs due to AA and DHA quantitative changes. In the case of AA increase in some tissues there is observed the decrease of docosapentaenic acid and increase of DHA and eucosapentaenic (EPA) acidds. As a result of studying FA content in the individual PL composition it has been identified that certain PL classes characteristic for some tissues respond by changes of some certain FA. The relationship omega 6/omega 3 has been shown as decreasing in phosphatidilcholine (PC) all tissues microsomes (liver, gonads, heart, brain), in phosphatidilethanolamine (PEA) of liver and cardiac microsomes, in phosphatidilserine (PS) this relationship relationship decreases in the liver, brain and heart, for phosphatidilinositole (PI) the changes take place in liver, gonads, brain. Simultaneously, the decrease of AA/DHA relationship in the individual PL decrease of AA and increase of EPA and DHA depend on the tested tissues. The marine phospholipids might be supposed to render their effect on AA metabolism resulting in AA/DHA relationship in PEA and PS relationship displays itself as specific and depends on the tissues functions. The preference of PEA and PS use by certain tissues microsomes could be explained by their membrane protective capability.     

Keloids in rural black South Africans. Part 2: dietary fatty acid intake and total phospholipid fatty acid profile in the blood of keloid patients

In the second part of this study, emphasis is placed on nutritional intakes (fatty acids and micronutrients) and fatty acid intake and metabolism in the blood, respectively, according to a combined 24 h recall and standardized food frequency questionnaire analyses of keloid prone patients (n=10), compared with normal black South Africans (n=80), and total phospholipid blood (plasma and red blood cell ) analyses of keloid patients (n=20), compared with normal individuals (n=20). Lipid extraction and fractionation by standard procedures, total phospholipid (TPL) separation with thin layer chromatography, and fatty acid methyl ester analyses with gas liquid chromatography techniques were used. Since nutrition may play a role in several disease disorders, the purpose of this study was to confirm or refute a role for essential fatty acids (EFAs) in the hypothesis of keloid formations stated in part 1 of this study. (1)According to the Canadian recommendation (1991), we observed that in keloid patients linoleic acid (LA) and arachidonic acid (AA) dietary intakes, as EFAs of the omega-6-series, are higher than the recommended 7-11 g/d. However, the a-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) dietary intakes, as EFAs of the omega-3 series, are lower than the recommendation of 1.1-1.5 g/d. This was also the case in the control group, where a higher dietary intake of the omega-6 fatty acids and a slightly lower dietary intake of the omega-3 fatty acids occurred. Thus, we confirm a high dietary intake of LA (as a product of organ meats, diary products and many vegetable oils) and AA (as a product of meats and egg yolks), as well as lower dietary intakes of ALA (as a product of grains, green leafy vegetables, soy oil, rapeseed oil and linseed), and EPA and DHA (as products of marine oils). Lower micronutrient intakes than the recommended dietary allowances were observed in the keloid group that may influence EFA metabolism and/or collagen synthesis. Of cardinal importance may be the lower intake of calcium in the keloid patients that may contribute to abnormal cell signal transduction in fibroblasts and consequent collagen overproduction, and the lower copper intake that may influence the immune system, or perhaps even the high magnesium intake that stimulates metabolic activity. Micronutrient deficiencies also occurred in the diets of the normal black South Africans that served as a control group. In the case of plasma TPLs, deficiency of the omega-3 EFA series (ALA, EPA and DHA) occurred, and this is in accordance with the apparent lower omega-3 EFA intake in the diets of these patients. In the case of the red blood cell TPLs, as a true and reliable source of dietary fatty acid intake and metabolism, sufficient EFAs of the omega-6 series (LA and AA) and the omega-3 series (ALA, EPA and DHA) occurred. For this study group a relative deficiency of nutritional omega-3 EFA intake apparently did occur, but was probably compensated for by blood fatty acid metabolism.     

Docosahexaenoic acid: one molecule diverse functions

Docosahexaenoic acid (DHA, C22:6, ω-3) is a highly polyunsaturated omega-3 fatty acid. It is concentrated in neuronal brain membranes, for which reason it is also referred to as a “brain food”. DHA is essential for brain development and function. It plays an important role in improving antioxidant and cognitive activities of the brain. DHA deficiency occurs during aging and dementia, impairs memory and learning, and promotes age-related neurodegenerative diseases, including Alzheimer’s disease (AD). For about two decades, we have reported that oral administration of DHA increases spatial memory acquisition, stimulates neurogenesis, and protects against and reverses memory impairment in amyloid β peptide-infused AD rat models by decreasing amyloidogenesis and protects against age-related cognitive decline in the elderly. These results demonstrate a robust link between DHA and cognitive health. Rodents that were fed a diet low in ω-3 polyunsaturated fatty acids, particularly those that were DHA-deficient, frequently suffered from anxiety, depression and memory impairment. Although the exact mechanisms of action of DHA in brain functions are still elusive, a host of mechanisms have been proposed. For example, DHA, which inherently has a characteristic three-dimensional structure, increases membrane fluidity, strengthens antioxidant activity and enhances the expression of several proteins that act as substrates for improving memory functions. It reduces the brain amyloid burden and inhibits in vitro fibrillation and amyloid-induced neurotoxicity in cell-culture model. In this review, we discuss how DHA acts as a molecule with diverse functions.     

Effects of long-chain polyunsaturated fatty acid supplementation on neurodevelopment in childhood: A review of human studies

Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA) are critical for infant and childhood brain development, but levels of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are often low in the Western diet. Increasing evidence from both epidemiological and intervention studies, reviewed here, indicates that DHA supplementation, during pregnancy, lactation, or childhood plays an important role in childhood neurodevelopment. Arachidonic acid (ARA) is also important for infant growth and development. Several studies have demonstrated positive associations between blood DHA levels and improvements on tests of cognitive and visual function in healthy children. Controlled trials also have shown that supplementation with DHA and EPA may help in the management of childhood psychiatric disorders, and improve visual and motor functions in children with phenylketonuria. In all studies, DHA and EPA supplementation is typically well tolerated. Further research is needed to determine optimal doses for efficacy at different developmental ages. The potential long-term benefits of early LCPUFA supplementation also require consideration.     

Docosahexaenoic acid neurolipidomics

Mediator lipidomics is a field of study concerned with the characterization, structural elucidation and bioactivity of lipid derivatives actively generated by enzymatic activity. It is well known that omega-3 fatty acids are beneficial for brain function. Docosahexaenoic acid [DHA; 4 22:6(n-3)] is the most abundant essential omega-3 fatty acid present in the brain and it has multiple mechanisms of exerting protective effects after cellular injury. Certain lipid species produced from DHA early during the reperfusion stage of brain ischemia-reperfusion injury are generated in order to help the cell cope as the injury progresses. We explore these newly discovered lipid mediators in order to understand their role in the cell. We have identified one of these potentially protective lipid mediators as a novel stereospecific DHA-derived fatty acid, called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z hexaenoic acid). DHA also has important roles in pro-survival signaling cascades after ischemia-reperfusion in injury. It has been shown to accelerate AKT translocation and activation and has binding affinity with an important PPAR-γ family of ligand-activated nuclear receptors that have been implicated in various aspects of lipid metabolism and have been shown to have anti-inflammatory actions. Here we present an overview of these mechanisms and discuss the potential of using DHA signaling in the development of treatments for the large population of patients suffering from the devastating consequences of stroke.     

Maternal and fetal brain contents of docosahexaenoic acid (DHA) and arachidonic acid (AA) at various essential fatty acid (EFA), DHA and AA dietary intakes during pregnancy in mice

We investigated essential fatty acids (EFA) and long-chain polyunsaturated fatty acids (LCP) in maternal and fetal brain as a function of EFA/LCP availability to the feto-maternal unit in mice. Diets varying in parent EFA, arachidonic acid (AA), and docosahexaenoic acid (DHA) were administered from day 3 prior to conception till day 15 of pregnancy. We concentrated on DHA, AA, Mead acid, and EFA-index [(omega-3+omega-6)/(omega-7+omega-9)] in maternal erythrocytes, maternal brain, and fetal brain. It was found that erythrocyte EFA/LCP sensitively reflects declining EFA/LCP status in pregnancy, although this decline was not apparent in maternal brain. Differences in erythrocyte EFA/LCP coincided with larger differences in fetal brain EFA/LCP as compared to EFA/LCP in maternal brain. Both maternal and fetal brains were affected by short-term EFA/LCP intake, but the developing fetal brain proved most sensitive. The inverse relationship between fetal brain AA and DHA suggests the need of a maternal dietary DHA/AA balance, at least in mice.     

Omega-3 fatty acids, energy substrates, and brain function during aging

The maintenance of optimal cognitive function is a central feature of healthy aging. Impairment in brain glucose uptake is common in aging associated cognitive deterioration, but little is known of how this problem arises or whether it can be corrected or bypassed. Several aspects of the challenge to providing the brain with an adequate supply of fuel during aging seem to relate to omega-3 fatty acids. For instance, low intake of omega-3 fatty acids, especially docosahexaenoic acid (DHA), is becoming increasingly associated with several forms of cognitive decline in the elderly, particularly Alzheimer's disease. Brain DHA level seems to be an important regulator of brain glucose uptake, possibly by affecting the activity of some but not all the glucose transporters. DHA synthesis from either alpha-linolenic acid (ALA) or eicosapentaenoic acid (EPA) is very low in humans begging the question of whether these DHA precursors are likely to be helpful in maintaining cognition during aging. We speculate that ALA and EPA may well have useful supporting roles in maintaining brain function during aging but not by their conversion to DHA. ALA is an efficient ketogenic fatty acid, while EPA promotes fatty acid oxidation. By helping to produce ketone bodies, the effects of ALA and EPA could well be useful in strategies intended to use ketones to bypass problems of impaired glucose access to the brain during aging. Hence, it may be time to consider whether the main omega-3 fatty acids have distinct but complementary roles in brain function.     

Dietary alpha linolenic acid in pregnant mice and during weaning increases brain docosahexaenoic acid and improves recognition memory in the offspring

Docosahexaenoic acid (DHA) is critical for normal brain development and function. DHA is in danger of being significantly reduced in the human food supply, and the question of whether its metabolic precursor, the essential n-3 alpha linolenic acid (ALA) during pregnancy, can support fetal brain DHA levels for optimal neurodevelopment, is fundamental.Female mice were fed either ALA-enriched or Control diet during pregnancy and lactation. The direct effect of maternal dietary ALA on lipids was analyzed in liver, red blood cells, brain and brain vasculature, together with genes of fatty acid metabolism and transport in three-week-old offspring. The long-term effect of maternal dietary ALA on brain fatty acids and memory was studied in 19-week-old offspring.Three-week-old ALA offspring showed higher levels of n-3 fatty acids in liver, red blood cell, blood-brain barrier (BBB) vasculature and brain parenchyma, DHA enrichment in brain phospholipids and higher gene and protein expression of the DHA transporter, major facilitator superfamily domain containing 2a, compared to Controls. 19-week-old ALA offspring showed higher brain DHA levels and better memory performance than Controls.The increased brain DHA levels induced by maternal dietary ALA during pregnancy-lactation, together with the up-regulated levels of major facilitator superfamily domain containing 2a, may indicate a mode for greater DHA uptake with long-term impact on better memory in ALA offspring.