Docosahexaenoic acid and synaptic protection in Alzheimer's disease mice

Alzheimer's disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Amyloid-beta (Aβ) oligomers are considered the proximate effectors in the early stages of AD. AD-related cognitive impairment, synaptic loss and neurodegeneration result from interactions of Aβ oligomers with the synaptic membrane and subsequent activation of pro-apoptotic signalling pathways. Therefore, membrane structure and lipid status appear determinant in Aβ-induced toxicity. Numerous epidemiological studies have highlighted the beneficial influence of docosahexaenoic acid (DHA, C22:6 n-3) on the preservation of synaptic function and memory capacities in aged individuals or upon Aβ exposure, whereas its deficiency is presented as a risk factor for AD. An elevated number of studies have been reporting the beneficial effects of dietary DHA supplementation on cognition and synaptic integrity in various AD models. In this review, we describe the important potential of DHA to preserve neuronal and brain functions and classified its numerous molecular and cellular effects from impact on membrane lipid content and organisation to activation of signalling pathways sustaining synaptic function and neuronal survival. DHA appears as one of the most valuable diet ingredients whose neuroprotective properties could be crucial for designing nutrition-based strategies able to prevent AD as well as other lipid- and age-related diseases whose prevalence is progressing in elderly populations.     

Phosphatidylserine in the brain: Metabolism and function

Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.     

Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing

The fluidity of neuronal membranes plays a pivotal role in brain aging and neurodegeneration. In this study, we investigated the role of the omega-3 fatty acid docosahexaenoic acid (DHA) in modulation of membrane fluidity, APP processing, and protection from cytotoxic stress. To this end, we applied unilamellar transfer liposomes, which provided protection from oxidation and effective incorporation of DHA into cell membranes. Liposomes transferring docosanoic acid (DA), the completely saturated form of DHA, to the cell cultures served as controls. In HEK-APP cells, DHA significantly increased membrane fluidity and non-amyloidogenic processing of APP, leading to enhanced secretion of sAPPα. This enhanced secretion of sAPPα was associated with substantial protection against apoptosis induced by ER Ca(2+) store depletion. sAPPα-containing supernatants obtained from HEK-APP cells exerted similar protective effects as DHA in neuronal PC12 cells and HEK293 control cells. Correlating to further increased sAPPα levels, supernatants obtained from DHA-treated HEK-APP cells enhanced protection, whereas supernatants obtained from DHA-treated HEK293 control cells did not inhibit apoptosis, likely due to the low expression of endogenous APP and negligible sAPPα secretion in these cells. Further experiments with the small molecule inhibitors LY294002 and SP600125 indicated that sAPPα-induced cytoprotection relied on activation of the anti-apoptotic PI3K/Akt pathway and inhibition of the stress-triggered JNK signaling pathway in PC12 cells. Our data suggest that liposomal DHA is able to restore or maintain physiological membrane properties, which are required for neuroprotective sAPPα secretion and autocrine modulation of neuronal survival.     

Endogenous Signaling by Omega-3 Docosahexaenoic Acid-derived Mediators Sustains Homeostatic Synaptic and Circuitry Integrity

The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA to sustain neuronal function and protect synapses and circuits in the context of DHA signalolipidomics. DHA signalolipidomics comprises the integration of the cellular/tissue mechanism of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains containing DHA phospholipids, and the precise cellular and molecular events revealed by the uncovering of signaling pathways regulated by docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore, this approach offers emerging targets for prevention, pharmaceutical intervention, and clinical translation involving DHA-mediated signaling.     

Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies

Studies in animals clearly show that oral intake of docosahexaenoic acid (DHA) can alter brain DHA concentrations and thereby modify brain functions. This provides us with an opportunity to use DHA as a nutraceutical or pharmaceutical tool in brain disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Most of the published epidemiological studies are consistent with a positive association between high reported DHA consumption or high DHA blood levels and a lower risk of developing AD later in life. Such observations have prompted the investigation of DHA in three different transgenic models of AD. These analyses show that animal models of AD are more vulnerable to DHA depletion than controls and that DHA exerts a beneficial effect against pathological signs of AD, including A beta accumulation, cognitive impairment, synaptic marker loss, and hyperphosphorylation of tau. Multiple mechanisms of action can be associated with the neuroprotective effects of DHA and include antioxidant properties and activation of distinct cell signaling pathways. Although the first randomized clinical assays have yet failed to demonstrate convincing beneficial effects of DHA for AD patients, the knowledge gathered in recent years holds out a hope for prevention and suggests that the elderly and people bearing a genetic risk for AD should at least avoid DHA deficiency.     

Biological action of docosahexaenoic acid in a 3D tissue-engineered psoriatic skin model: Focus on the PPAR signaling pathway

N-3 polyunsaturated fatty acids (n-3 PUFAs), and in particular docosahexaenoic acid (DHA), have many beneficial metabolic effects, including reducing epidermal thickness in patients with psoriasis. The positive impacts of DHA in psoriasis could be mediated by its interactions with the PPAR signaling pathway, as well as by its secretion of anti-inflammatory bioactive metabolites, but the detailed metabolism is still not understood. In the present study, we evaluated the influence of DHA on the main features of psoriasis and its effects on the PPAR signaling pathway, in a psoriatic in vitro skin model. Healthy and psoriatic skin substitutes were produced according to the tissue-engineered self-assembly method, using culture media supplemented with 10 μM of DHA. The presence of DHA led to a reduction in the abnormal cell differentiation of psoriatic keratinocytes, seen in the increased expression of filaggrin and keratin 10. DHA was incorporated into the membrane phospholipids of the epidermis and transformed principally into eicosapentaenoic acid (EPA). Furthermore, the addition of DHA into the culture medium led to a decrease in the levels of lipid mediators derived from n-6 PUFAs, mainly prostaglandin E₂ (PGE₂) and 12-hydroxyeicosatetraenoic acid (12-HETE). Finally, DHA supplementation rebalanced the expression of PPAR receptors and caused a decrease in the secretion of TNF-α. Altogether, our results show that DHA possesses the ability to attenuate the psoriatic characteristics of psoriatic skin substitutes, mostly by restoring epidermal cell differentiation and proliferation, as well as by reducing inflammation.     

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.     

Nutritional n-3 polyunsaturated fatty acids deficiency alters cannabinoid receptor signaling pathway in the brain and associated anxiety-like behavior in mice

N-3 polyunsaturated fatty acids (PUFAs) cannot be synthesized de novo in mammals and need to be provided by dietary means. In the brain, the main n-3 PUFA is docosahexaenoic acid (DHA), which is a key component of neuronal membranes. A low dietary level of DHA has been associated with increased risk of developing neuropsychiatric diseases; however, the mechanisms involved remain to be determined. In this study, we found that long-term exposure to an n-3 deficient diet decreases the level of DHA in the brain and impairs the cannabinoid receptor signaling pathway in mood-controlling structures. In n-3 deficient mice, the effect of the cannabinoid agonist WIN55,212-2 in an anxiety-like behavior test was abolished. In addition, the cannabinoid receptor signaling pathways were altered in the prefrontal cortex and the hypothalamus. Consequently, our data suggest that behavioral changes linked to an n-3 dietary deficiency are due to an alteration in the endocannabinoid system in specific brain areas.     

Omega-3 Essential Fatty Acids Modulate Initiation and Progression of Neurodegenerative Disease

The significance of the selective enrichment in omega-3 essential fatty acids in photoreceptors and synaptic membranes of the nervous system has remained, until recently, incompletely understood. While studying mechanisms of cell survival in neural degeneration, we discovered a docosanoid synthesized from unesterified docosahexaenoic acid (DHA) by a 15-lipoxygenase (15-LOX), which we called neuroprotectin D1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15E,19Z hexaenoic acid). This lipid mediator is a docosanoid because it is derived from the 22 carbon (22C) precursor DHA, unlike eicosanoids, which are derived from the 20 carbon (20C) arachidonic acid (AA) family member of essential fatty acids. We discovered that NPD1 is promptly made in response to oxidative stress, as a response to brain ischemia–reperfusion, and in the presence of neurotrophins. NPD1 is neuroprotective in experimental brain damage, in oxidative-stressed retinal pigment epithelial (RPE) cells, and in human brain cells exposed to amyloid-β (Aβ) peptides. We thus envision NPD1 as a protective sentinel, one of the very first defenses activated when cell homeostasis is threatened by imbalances in normal neural function. We provide here, in three sections, recent experimental examples that highlight the specificity and potency of NPD1 spanning beneficial bioactivity during initiation and early progression of neurodegeneration: (1) during retinal signal phototransduction, (2) during brain ischemia–reperfusion, and (3) in Alzheimer's disease (AD) and stressed human brain cell models of AD. From this experimental evidence, we conclude that DHA-derived NPD1 regulation targets upstream events of brain cell apoptosis, as well as neuro-inflammatory signaling, promoting and maintaining cellular homeostasis, and restoring neural and retinal cell integrity.     

Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood

Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders.     

Docosahexaenoic acid (DHA) sensitizes brain tumor cells to etoposide-induced apoptosis

In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFκB1, NFκBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16.     

Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling

The special glycerophospholipids plasmalogens (Pls) are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor) proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh)-RNA lentiviral particles revealed that the Pls-mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system.     

Omega-3 fatty acids in neurodegenerative diseases: Focus on mitochondria

Mitochondrial dysfunction represents a common early pathological event in brain aging and in neurodegenerative diseases, e.g., in Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s disease (HD), as well as in ischemic stroke. In vivo and ex vivo experiments using animal models of aging and AD, PD, and HD mainly showed improvement of mitochondrial function after treatment with polyunsaturated fatty acids (PUFA) such as docosahexaenoic acid (DHA). Thereby, PUFA are particular beneficial in animals treated with mitochondria targeting toxins. However, DHA showed adverse effects in a transgenic PD mouse model and it is not clear if a diet high or low in PUFA might provide neuroprotective effects in PD. Post-treatment with PUFA revealed conflicting results in ischemic animal models, but intravenous administered DHA provided neuroprotective efficacy after acute occlusion of the middle cerebral artery. In summary, the majority of preclinical data indicate beneficial effects of n-3 PUFA in neurodegenerative diseases, whereas most controlled clinical trials did not meet the expectations. Because of the high half-life of DHA in the human brain clinical studies may have to be initiated much earlier and have to last much longer to be more efficacious.     

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.     

Modulation of enzymatic activities by n-3 polyunsaturated fatty acids to support cardiovascular health

Epidemiological evidence from Greenland Eskimos and Japanese fishing villages suggests that eating fish oil and marine animals can prevent coronary heart disease. Dietary studies from various laboratories have similarly indicated that regular fish oil intake affects several humoral and cellular factors involved in atherogenesis and may prevent atherosclerosis, arrhythmia, thrombosis, cardiac hypertrophy and sudden cardiac death. The beneficial effects of fish oil are attributed to their n-3 polyunsaturated fatty acid (PUFA; also known as omega-3 fatty acids) content, particularly eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Dietary supplementation of DHA and EPA influences the fatty acid composition of plasma phospholipids that, in turn, may affect cardiac cell functions in vivo. Recent studies have demonstrated that long-chain omega-3 fatty acids may exert beneficial effects by affecting a wide variety of cellular signaling mechanisms. Pathways involved in calcium homeostasis in the heart may be of particular importance. L-type calcium channels, the Na+-Ca2+ exchanger and mobilization of calcium from intracellular stores are the most obvious key signaling pathways affecting the cardiovascular system; however, recent studies now suggest that other signaling pathways involving activation of phospholipases, synthesis of eicosanoids, regulation of receptor-associated enzymes and protein kinases also play very important roles in mediating n-3 PUFA effects on cardiovascular health. This review is therefore focused on the molecular targets and signaling pathways that are regulated by n-3 PUFAs in relation to their cardioprotective effects.     

Eicosapentaenoic acid induces neovasculogenesis in human endothelial progenitor cells by modulating c-kit protein and PI3-K/Akt/eNOS signaling pathways

Human endothelial progenitor cells (hEPCs) derived from bone marrow play a crucial in the prevention of ischemic injuries in the course of postnatal neovasculogenesis. Frequent fish oil (FO) consumption is reportedly associated with a significantly lower incidence of cardiovascular disease. However, the molecular mechanisms of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) are not well elucidated, and the beneficial effect of FO consumption on neovasculogenesis has not been demonstrated yet. In the current study, we investigated the effects of EPA/DHA and FO consumption on neovasculogenesis by using vascular tube formation assay, Western blotting, real-time polymerase chain reaction, immunohistochemical staining and Doppler imaging in both in vitro and in vivo models. The results demonstrate that EPA and DHA dose-dependently enhance the neovasculogenesis and cell migration of hEPCs in vitro. The mechanisms of action included up-regulation of the c-kit protein as well as the phosphorylation of the ERK1/2, Akt and endothelial nitric oxide synthase signaling molecules in hEPCs. Furthermore, EPA significantly suppressed the expression of microRNA 221 in vitro. In experimental animal models, FO consumption significantly induced the formation of new blood vessels (neovasculogenesis) and prevented ischemia. Taken together, it is suggested that FO consumption enhances neovasculogenesis mainly through the effects of EPA in hEPCs, thereby exerting a preventive effect against ischemic injury.     

<Emphasis Type="Italic">S</Emphasis>-Nitrosylation Regulates Cell Survival and Death in the Central Nervous System

Nitric oxide (NO), which is produced from nitric oxide synthase, is an important cell signaling molecule that is crucial for many physiological functions such as neuronal death, neuronal survival, synaptic plasticity, and vascular homeostasis. This diffusible gaseous compound functions as an effector or second messenger in many intercellular communications and/or cell signaling pathways. Protein S-nitrosylation is a posttranslational modification that involves the covalent attachment of an NO group to the thiol side chain of select cysteine residues on target proteins. This process is thought to be very important for the regulation of cell death, cell survival, and gene expression in the central nervous system (CNS). However, there have been few reports on the role of protein S-nitrosylation in CNS disorders. Here, we briefly review specific examples of S-nitrosylation, with particular emphasis on its functions in neuronal cell death and survival. An understanding of the role and mechanisms underlying the effects of protein S-nitrosylation on neurodegenerative/neuroprotective events may reveal a novel therapeutic strategy for rescuing neurons in neurodegenerative diseases.     

Biochemical and biological functions of docosahexaenoic acid in the nervous system: modulation by ethanol

Docosahexaenoic acid (DHA, 22:6n-3), an n-3 fatty acid highly concentrated in the central nervous system, is essential for proper neuronal and retinal function. While a high level of DHA is generally maintained in neuronal membranes, inadequate supply of n-3 fatty acid or ethanol exposure leads to a significant loss of DHA in neuronal cells. The roles of DHA in neuronal signaling have been emerging. In this review, biological, biochemical and molecular mechanisms supporting the essential function of DHA in neuronal survival and development are described in relation to n-3 fatty acid depleting conditions.     

Dietary Docosahexaenoic Acid Supplementation Modulates Hippocampal Development in the Pemt?/? Mouse

The development of fetal brain is influenced by nutrients such as docosahexaenoic acid (DHA, 22:6) and choline. Phosphatidylethanolamine-N-methyltransferase (PEMT) catalyzes the biosynthesis of phosphatidylcholine from phosphatidylethanolamine enriched in DHA and many humans have functional genetic polymorphisms in the PEMT gene. Previously, it was reported that Pemt^−/− mice have altered hippocampal development. The present study explores whether abnormal phosphatidylcholine biosynthesis causes altered incorporation of DHA into membranes, thereby influencing brain development, and determines whether supplemental dietary DHA can reverse some of these changes. Pregnant C57BL/6 wild type (WT) and Pemt^−/− mice were fed a control diet, or a diet supplemented with 3 g/kg of DHA, from gestational day 11 to 17. Brains from embryonic day 17 fetuses derived from Pemt^−/− dams fed the control diet had 25–50% less phospholipid-DHA as compared with WT (p < 0.05). Also, they had 60% more neural progenitor cell proliferation (p < 0.05), 60% more neuronal apoptosis (p < 0.01), and 30% less calretinin expression (p < 0.05; a marker of neuronal differentiation) in the hippocampus compared with WT. The DHA-supplemented diet increased fetal brain Pemt^−/− phospholipid-DHA to WT levels, and abrogated the neural progenitor cell proliferation and apoptosis differences. Although this diet did not change proliferation in the WT group, it halved the rate of apoptosis (p < 0.05). In both genotypes, the DHA-supplemented diet increased calretinin expression 2-fold (p < 0.05). These results suggest that the changes in hippocampal development in the Pemt^−/− mouse could be mediated by altered DHA incorporation into membrane phospholipids, and that maternal dietary DHA can influence fetal brain development.