Polyunsaturated Fatty Acids In Brain Research Articles

Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain-Study in a Mouse Model of the Disease.

Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p < 0.0001), and in the bran, decreased 8-isoprostane amounts (p < 0.0001), increased resolvin D1 levels (p < 0.005) and increased quantity of total n-3 PUFAs (p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = -0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = -0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.

Elucidation of the pathology of mental disorders focusing on polyunsaturated fatty acids and FABPs

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function, and an imbalance of brain PUFAs is linked to mental disorders like autism and schizophrenia. However, the cellular and molecular mechanisms underlying the effects of PUFAs on the brain remain largely unknown. Since they are insoluble in water, specific transporters like fatty acid binding proteins (FABPs), are required for transport and function of PUFAs within cells. We focused on the relationship between FABP-mediated homeostasis of brain PUFAs and neural plasticity. We found that FABP3, with a high affinity for n-6 PUFAs, is predominantly expressed in the GABAergic inhibitory interneurons of the anterior cingulate cortex (ACC) in the adult mouse brain. FABP3 knockout (KO) mice show increased GABA synthesis and inhibitory synaptic transmission in the ACC. We also found that FABP7 controls lipid raft function in astrocytes, and astrocytes lacking FABP7 exhibit changes in response to external stimuli. Furthermore, in FABP7 KO mice, dendritic protrusion formation in pyramidal neurons becomes abnormal, and we have reported a decrease in spine density and excitatory synaptic transmission. Here, we introduced recent advances in the understanding of the functions of PUFAs and FABPs in the brain, focusing especially on FABP3 and FABP7, in relation to human mental disorders.

Mice prenatally exposed to valproic acid do not show autism-related disorders when fed with polyunsaturated fatty acid-enriched diets

Dietary supplementations with n-3 polyunsaturated fatty acid (PUFA) have been explored in autism spectrum disorder (ASD) but their efficiency and potential in ameliorating cardinal symptoms of the disease remain elusive. Here, we compared a n-3 long-chain (LC) PUFA dietary supplementation (n-3 supp) obtained from fatty fish with a n-3 PUFA precursor diet (n-3 bal) obtained from plant oils in the valproic acid (VPA, 450 mg/kg at E12.5) ASD mouse model starting from embryonic life, throughout lactation and until adulthood. Maternal and offspring behaviors were investigated as well as several VPA-induced ASD biological features: cerebellar Purkinje cell (PC) number, inflammatory markers, gut microbiota, and peripheral and brain PUFA composition. Developmental milestones were delayed in the n-3 supp group compared to the n-3 bal group in both sexes. Whatever the diet, VPA-exposed offspring did not show ASD characteristic alterations in social behavior, stereotypies, PC number, or gut microbiota dysbiosis while global activity, gait, peripheral and brain PUFA levels as well as cerebellar TNF-alpha levels were differentially altered by diet and treatment according to sex. The current study provides evidence of beneficial effects of n-3 PUFA based diets, including one without LCPUFAs, on preventing several behavioral and cellular symptoms related to ASD.

Curcumin in diet modulates fatty acid levels and mRNA expression of appetite-regulating neuropeptides in brain and enhances growth via the GH-GHR-IGF axis in tilapia, Oreochromis mossambicus.

Curcumin in 0.5% and 1% doses was given as a feed additive to tilapia (Oreochromis mossambicus) for 100 days to evaluate the effect of curcumin on fatty acid levels in brain, appetite and the growth axis-related gene expressions. A total of 180 fish were randomly stocked into 650 l tanks and fed with basal feed during acclimatization. Three treatment groups were established, each having three replicates and each replicate had 20 fish. They were fed twice on the experimental diets of 10% body weight ration per fish. Gas chromatography analysis revealed a significant change in the amount of total saturated fatty acids and total monounsaturated fatty acids in tilapia brain. The present study indicated an increase in n-3 (omega-3) and n-6 (omega-6) polyunsaturated fatty acids in brain. Real-time quantification of appetite-regulating neuropeptides in brain and growth-related gene expressions in muscle revealed a significant modulation in their mRNA expressions. This information obtained in the present study on the beneficial role of curcumin in the regulation of fatty acid levels and the expression of appetite-regulating neuropeptides and growth-regulating factors will contribute to research in feed intake and growth in fish.

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling.

Increasing evidence supports a relationship between lipid metabolism and mental health. In particular, the biostatus of polyunsaturated fatty acids (PUFAs) correlates with some symptoms of psychiatric disorders, as well as the efficacy of pharmacological treatments. Recent findings highlight a direct association between brain PUFA levels and dopamine transmission, a major neuromodulatory system implicated in the etiology of psychiatric symptoms. However, the mechanisms underlying this relationship are still unknown. Here we demonstrate that membrane enrichment in the n-3 PUFA docosahexaenoic acid (DHA), potentiates ligand binding to the dopamine D2 receptor (D2R), suggesting that DHA acts as an allosteric modulator of this receptor. Molecular dynamics simulations confirm that DHA has a high preference for interaction with the D2R and show that membrane unsaturation selectively enhances the conformational dynamics of the receptor around its second intracellular loop. We find that membrane unsaturation spares G protein activity but potentiates the recruitment of β-arrestin in cells. Furthermore, in vivo n-3 PUFA deficiency blunts the behavioral effects of two D2R ligands, quinpirole and aripiprazole. These results highlight the importance of membrane unsaturation for D2R activity and provide a putative mechanism for the ability of PUFAs to enhance antipsychotic efficacy.

Lipids and brain inflammation in APOE4-associated dementia.

To highlight recent developments in studying mechanisms by which the apolipoprotein E4 (APOE4) allele affects the metabolism of brain lipids and predisposes the brain to inflammation and Alzheimer's disease (AD) dementia. APOE4 activates Ca2+ dependent phospholipase A2 (cPLA2) leading to changes in arachidonic acid (AA), eicosapentaenoic acid and docosahexaenoic acid signaling cascades in the brain. Among these changes, the increased conversion of AA to eicosanoids associates with sustained and unresolved chronic brain inflammation. The effects of APOE4 on the brain differ by age, disease stage, nutritional status and can be uncovered by brain imaging studies of brain fatty acid uptake. Reducing cPLA2 expression in the dementia brain presents a viable strategy that awaits to be tested. Fatty acid brain imaging techniques can clarify how changes to brain polyunsaturated fatty acid metabolism during the various phases of AD and guide the development of small molecules to mitigate brain inflammation.

Tissue pretreatment for LC\u2013MS/MS analysis of PUFA and eicosanoid distribution in mouse brain and liver

Polyunsaturated fatty acids (PUFAs) and eicosanoids are important mediators of inflammation. The functional role of eicosanoids in metabolic-syndrome-related diseases has been extensively studied. However, their role in neuroinflammation and the development of neurodegenerative diseases is still unclear. The aim of this study was the development of a sample pretreatment protocol for the simultaneous analysis of PUFAs and eicosanoids in mouse liver and brain. Liver and brain samples of male wild-type C57BL/6J mice (11–122 mg) were used to investigate conditions for tissue rinsing, homogenization, extraction, and storage. A targeted liquid chromatography–negative electrospray ionization tandem mass spectrometry method was applied to quantify 7 PUFAs and 94 eicosanoids. The final pretreatment protocol consisted of a 5-min homogenization step by sonication in 650 μL n-hexane/2-propanol (60:40 v/v) containing 2,6-di-tert-butyl-4-methylphenol at 50 μg/mL. Homogenates representing 1 mg tissue were extracted in a single step with n-hexane/2-propanol (60:40 v/v) containing 0.1% formic acid. Autoxidation was prevented by addition of 2,6-di-tert-butyl-4-methylphenol at 50 μg/mL and keeping the samples at 4 °C during sample preparation. Extracts were dried under nitrogen and reconstituted in liquid chromatography eluent before analysis. Recovery was determined to range from 45% to 149% for both liver and brain tissue. Within-run and between-run variability ranged between 7% and 18% for PUFAs and between 1% and 24% for eicosanoids. In liver, 7 PUFAs and 15 eicosanoids were quantified; in brain, 6 PUFAs and 21 eicosanoids had significant differences within the brain substructures. In conclusion, a robust and reproducible sample preparation protocol for the multiplexed analysis of PUFAs and eicosanoids by liquid chromatography–tandem mass spectrometry in liver and discrete brain substructures was developed.

Possible involvement of PKC/MAPK pathway in the regulation of GnRH by dietary arachidonic acid in the brain of male tongue sole Cynoglossus semilaevis

Our previous studies have indicated that dietary arachidonic acid (ARA) significantly affects the gonadal steroidogenesis in the marine teleost tongue sole Cynoglossus semilaevis, and this effect was more positive in male fish than in female fish (Aquaculture, 468, 378–385). As a following up study, the present study was further aimed at investigating the possible mechanisms in the brain mediating the effects of dietary ARA on gonadal steroidogenesis. A 70-day feed trial was repeated with two-year-old tongue sole, using three experimental diets with graded levels of ARA, 0.34%, 2.53%, and 9.63% of total fatty acids. Each diet was fed to triplicate groups of 23 fish (15 males and 8 females). The results confirmed the positive effect of dietary ARA on testosterone production in male fish. The concentration of gonadotrophin-releasing hormone (GnRH) in serum responded to dietary ARA in a similar pattern with the testosterone concentration, but the concentration of gonadotrophin in serum was not affected by dietary ARA. The response of gene expression of PKCβ, ARRB1, ARRB2, ERK2 and ATF3 in the brain to dietary ARA was in good agreement with those of GnRH and testosterone, indicating the possible involvement of PKC-ARRB-ERK-ATF3 pathway in signalling transduction of GnRH. However, the PI3K/Akt and TLR/NF-κB pathways may not be directly involved in the regulation of GnRH metabolism by ARA. This is the first study reporting the possible involvement of PKC/MAPK pathways in regulation of reproductive endocrine processes by long-chain polyunsaturated fatty acid in brain of marine fish.

Effect of Conjugated Linoleic Acid on Memory and Reflex Maturation in Rats Treated During Early Life.

In the critical period of neurodevelopment (gestation and lactation), maternal consumption of essential fatty acids (FAs) can alter the offspring cognitive function permanently causing damage. Lipids can regulate neurotrophin and compose brain tissue. However, the effects of maternal consumption of a mixture of conjugated linoleic acid (CLA) on an offspring nervous system are not completely clear. We aimed to investigate the impacts of different CLA concentrations mixed into the maternal diet during early life on neonatal reflex maturation and cognitive functions of the offspring. Three groups were formed: control (CG): receiving a standard diet; CLA1: receiving a diet containing 1% of CLA, and CLA3: receiving a diet containing 3% of CLA, offered during gestation and lactation. After birth, the reflex responses of the offspring were observed from the 1st to the 21st day. After weaning, the animals’ anxiety and memory were assessed using open field (OF) and novel object recognition tests. Fatty acids in the breast milk and the offspring’s brain were also quantified. The data were analyzed using one-way ANOVA and the Kruskal–Wallis test. CLA1 presented accelerated palmar grasp disappearance versus CLA3 and negative-geotaxis versus CG; and the CLA3 presented increases for most reflexes (cliff-avoidance, vibrissa-placing, negative-geotaxis, and auditory-startle response), and decrease in reflexes palmar grasp and free-fall righting versus CG (p < 0.05). CLA3 group explored less of the OF in the second exposure. CLA1 and CLA3 presented an increased exploration ratio for new objects, which indicates memory improvement. The milk tested from CLA3 demonstrated an increase in polyunsaturated fatty acids (PUFAs), and a decrease in monounsaturated fatty acids. The amount of CLA in milk was greater in CLA1 and CLA3 and in the brain offspring both presented moderated amounts of CLA. Maternal treatment with the CLA mixture induced anticipated reflex maturation and improved memory in the offspring. Even though CLA was detected in the brains in only trace amounts, offspring’s brain PUFA and SFA levels were increased. Further studies aimed to delineate the effect of maternal CLA supplementation on offspring’s brain lipid metabolism and long-term neurologic outcome are needed to confirm these findings.

Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T + Itpr3tf/J (BTBR) – a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial.

A diet enriched in longer chain omega-3 fatty acids reduced placental inflammatory cytokines and improved fetal sustainability of C57BL/6 mice

Omega (n)-3 polyunsaturated fatty acids (PUFA) are important regulators of inflammatory response that may impact pregnancy outcome. The effects of breeding chow diets containing n-3 PUFA from either fish oil (FO) or soybean oil (SO) were investigated on tissue fatty acid composition, inflammatory cytokines and pregnancy outcome. Female C57BL/6 mice (7 weeks old) were fed FO or SO diets for 2 weeks before mating and throughout pregnancy. Animals were sacrificed before and during pregnancy at day 6.5, 12.5 and 18.5. The FO diet increased the incorporation of n-3 PUFA in placenta, with a concomitant decrease in the concentration of pro-inflammatory cytokines. The FO diet increased the mRNA expression of placental specific PUFA transporter, which coincided with accretion of n-3 PUFA in fetal brain. Sites of fetal resorption were noticeable in the SO group but not in the FO group. N-3 PUFA may improve fetal sustainability via altering cytokine levels.

Dietary arachidonic acid: a Janus face actor in brain and Alzheimer’s disease?

Arachidonic acid is the second polyunsaturated fatty acid in brain and the first one belonging to the ω-6 series. Dietary intakes of arachidonic are between 50 and 300 mg/day in western diets but they might be underestimated. Triglycerides from fat would provide similar amounts than phospholipids of lean meat. Alzheimer’s disease is an age-associated degenerative disease and a critical health concern worldwide. Amyloid-β peptide oligomers are presently recognized as the main and earliest agents of Alzheimer’s disease although their neurotoxicity requires the presence of tau protein. We and others established that the arachidonic-specific cytosolic phospholipase A2is critical for the amyloid-β peptide oligomer neurotoxicity. Then, we showed that an arachidonic acid-rich diet increases the mouse sensitivity to the amyloid-β peptide oligomer deleterious effect without major increase of arachidonic acid levels in brain. This suggests that dietary arachidonic acid can exert its effects in brain through peripheral modifications. Involvement of systemic sub-inflammation and gut-brain communications are discussed based on the recent literature. The various data suggest that dietary arachidonic acid should be taken into account in the design of preventive strategies against Alzheimer’s disease.

Identifying Alzheimer's Disease Biomarkers by Analyzing Fatty Acids in Cerebrospinal Fluid and Urine

Although fatty acid oxidation is associated with Alzheimer's disease (AD) pathology, no links have been established between brain lipids and excreted oxidized products. We hypothesize that oxidation of brain polyunsaturated fatty acids (PUFA) can generate dicarboxylic acids (DCA) excreted in urine by AD subjects at different rates compared with cognitively healthy (CH) subjects. Furthermore, this trend can be extended to differentiate CH subjects with normal cerebrospinal fluid (CSF) Aβ42/tau ratios (CH‐NAT) and CH subjects with pathological CSF Aβ42/tau ratios (CH‐PAT).Subjects &gt; 70 years were classified as CH (n=64) or AD (n=26) after neuropsychological assessment. CSF Aβ42 and Tau levels were determined using an ELISA‐based method and a logistic regression of Aβ42/tau ratios used to classify CH‐NAT and CH‐PAT. CSF was fractionated and PUFA levels quantified in supernatant fluid (SF), nanoparticles (NP), and unesterified fatty acid (UFA). DCA was derivatized to pentafluorobenzyl ester, and quantified using gas chromatography and isotope dilution negative ion chemical ionization mass spectrometry. PUFA data is expressed as a percentage of fatty acids detected in CSF fractions while DCA is calculated as a percentage of 7 DCAs (C4–C10) in urine. Links between urinary DCAs and CSF PUFAs were determined using Spearman's ranked correlation.C10 DCA negatively correlated with 6 of 8 PUFAs in SF from CH and also negatively correlated with C20:3n‐3 and C22:6n‐3 in SF from CH‐NAT. In contrast, C9 DCA negatively correlated with 7 of 8 PUFAs in SF from AD. C6 and C8 DCAs positively correlated with SF C18:3n‐3 and C20:3n‐3 in AD, respectively, while C6 DCA negatively correlated with SF C18:2n‐6 from CH‐NAT. C4 DCA negatively correlated with C18:2n‐6, C20:4n‐6, and C22:6n‐3 in SF from CH‐PAT, while C7 DCA positively correlated with C20:4n‐6 in SF from CH‐PAT. In the NP fraction of CH, C4 DCA positively correlated with C20:2n‐6, C20:3n‐3, C20:5n‐3, and C22:5n‐3 PUFAs, while C8 DCA negatively correlated with C20:5n‐3. Only C9 DCA positively correlated with C20:4n‐6 in AD NP fractions. Interestingly, no correlations were found in the NP fraction from CH‐NAT. However, C8 DCA negatively correlated with NP C20:3n‐3, C20:5n‐3, and C22:5n‐3 and C4 DCA positively correlated with NP C20:5n‐3 from CH‐PAT. For UFA of CH, C6 DCA negatively correlated with C20:2n‐6, C20:3n‐3, and C22:6n‐3, while C5 and C7 DCAs positively correlated with homo‐γ‐C20:3n‐6 and C18:2n‐6, respectively. For UFA of CH‐NAT, C4 DCA positively correlated with homo‐γ‐C20:3n‐6, C5 and C8 DCAs negatively correlated with homo‐γ‐C20:3n‐6, and C7 DCA negatively correlated with C18:2n‐6. C5 DCA positively correlated with C18:2n‐6 in UFA from CH‐PAT. C8 DCA positively correlated with unesterified C22:6n‐3, while C9 DCA negatively correlated with unesterified C20:5n‐3 in AD subjects.Differential correlation of urinary DCAs with CSF PUFAs in clinical groups suggests a link with AD pathology. PUFAs and DCAs that segregate CH‐NAT from CH‐PAT are potential biomarkers of early AD.Support or Funding InformationL.K. Whittier and the Helen Posthuma FoundationsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Subcellular Distribution of Alpha-Tocopherol in the Adult Primate Brain and Its Relationship with Membrane Arachidonic Acid and Its Oxidation Products.

The relationship between α-tocopherol, a known antioxidant, and polyunsaturated fatty acid (PUFA) oxidation, has not been directly investigated in the primate brain. This study characterized the membrane distribution of α-tocopherol in brain regions and investigated the association between membrane α-tocopherol and PUFA content, as well as brain PUFA oxidation products. Nuclear, myelin, mitochondrial, and neuronal membranes were isolated using a density gradient from the prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC) of adult rhesus monkeys (n = 9), fed a stock diet containing vitamin E (α-, γ-tocopherol intake: ~0.7 µmol/kg body weight/day, ~5 µmol/kg body weight/day, respectively). α-tocopherol, PUFAs, and PUFA oxidation products were measured using high performance liquid chromatography (HPLC), gas chromatography (GC) and liquid chromatography-gas chromatography/mass spectrometry (LC-GC/MS) respectively. α-Tocopherol (ng/mg protein) was highest in nuclear membranes (p < 0.05) for all regions except HC. In PFC and ST, arachidonic acid (AA, µg/mg protein) had a similar membrane distribution to α-tocopherol. Total α-tocopherol concentrations were inversely associated with AA oxidation products (isoprostanes) (p < 0.05), but not docosahexaenoic acid oxidation products (neuroprostanes). This study reports novel data on α-tocopherol accumulation in primate brain regions and membranes and provides evidence that α-tocopherol and AA are similarly distributed in PFC and ST membranes, which may reflect a protective effect of α-tocopherol against AA oxidation.

Lutein accumulates in subcellular membranes of brain regions in adult rhesus macaques: Relationship to DHA oxidation products.

ObjectivesLutein, a carotenoid with anti-oxidant functions, preferentially accumulates in primate brain and is positively related to cognition in humans. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), is also beneficial for cognition, but is susceptible to oxidation. The present study characterized the membrane distribution of lutein in brain regions important for different domains of cognitive function and determined whether membrane lutein was associated with brain PUFA oxidation.MethodsAdult rhesus monkeys were fed a stock diet (~2 mg/day lutein or ~0.5 μmol/kg body weight/day) (n = 9) or the stock diet plus a daily supplement of lutein (~4.5 mg/day or~1 μmol/kg body weight/day) and zeaxanthin (~0.5 mg/day or 0.1 μmol/kg body weight/day) for 6–12 months (n = 4). Nuclear, myelin, mitochondrial, and neuronal plasma membranes were isolated using a Ficoll density gradient from prefrontal cortex (PFC), cerebellum (CER), striatum (ST), and hippocampus (HC). Carotenoids, PUFAs, and PUFA oxidation products were measured using HPLC, GC, and LC-GC/MS, respectively.ResultsAll-trans-lutein (ng/mg protein) was detected in all regions and membranes and was highly variable among monkeys. Lutein/zeaxanthin supplementation significantly increased total concentrations of lutein in serum, PFC and CER, as well as lutein in mitochondrial membranes and total DHA concentrations in PFC only (P<0.05). In PFC and ST, mitochondrial lutein was inversely related to DHA oxidation products, but not those from arachidonic acid (P <0.05).DiscussionThis study provides novel data on subcellular lutein accumulation and its relationship to DHA oxidation in primate brain. These findings support the hypothesis that lutein may be associated with antioxidant functions in the brain.

α-Synuclein structural features inhibit harmful polyunsaturated fatty acid oxidation, suggesting roles in neuroprotection

α-Synuclein (aS) is a protein abundant in presynaptic nerve terminals in Parkinson disease (PD) and is a major component of intracellular Lewy bodies, the pathological hallmark of neurodegenerative disorders such as PD. Accordingly, the relationships between aS structure, its interaction with lipids, and its involvement in neurodegeneration have attracted great interest. Previously, we reported on the interaction of aS with brain polyunsaturated fatty acids, in particular docosahexaenoic acid (DHA). aS acquires an α-helical secondary structure in the presence of DHA and, in turn, affects DHA structural and aggregative properties. Moreover, aS forms a covalent adduct with DHA. Here, we provide evidence that His-50 is the main site of this covalent modification. To better understand the role of His-50, we analyzed the effect of DHA on aS-derived species: a naturally occurring variant, H50Q; an oxidized aS in which all methionines are sulfoxides (aS4ox); a fully lysine-alkylated aS (acetyl-aS); and aS fibrils, testing their ability to be chemically modified by DHA. We show, by mass spectrometry and spectroscopic techniques, that H50Q and aS4ox are modified by DHA, whereas acetyl-aS is not. We correlated this modification with aS structural features, and we suggest a possible functional role of aS in sequestering the early peroxidation products of fatty acids, thereby reducing the level of highly reactive lipid species. Finally, we show that fibrillar aS loses almost 80% of its scavenging activity, thus lacking a potentially protective function. Our findings linking aS scavenging activity with brain lipid composition suggest a possible etiological mechanism in some neurodegenerative disorders.

The Effect of Membrane Polyunsaturated Fatty Acids on Receptor Partitioning to Ordered Domains

Numerous G protein-coupled receptors (GPCRs) contain cholesterol binding sites, and are therefore assumed to partition into cholesterol-rich ordered membrane domains to function properly. Neurotransmitter receptors - many of which are GPCRs and located mainly in the nervous system - are responsible for regulating our behavior and mood, and their compromised signaling often results in neurodegenerative diseases. Interestingly, many such diseases are associated with a decrease in polyunsaturated fatty acid (PUFA) levels in the brain.The PUFAs, usually paired with a saturated lipid tail in hybrid lipids, are known to favorably interact with receptors. This might - in addition to modulating the activation of individual receptors - also affect larger scale GPCR organization, including their partitioning between ordered and disordered membrane domains. However, such effects are very tedious to be studied experimentally, and therefore the determinants of membrane protein partitioning remain currently elusive.Here, using multi-scale computer simulations and free energy calculations, we show that the association of the adenosine A2A receptor, a prototypical GPCR, with the PUFA tail of a hybrid lipid drastically affects its partitioning. The strong PUFA-receptor interaction results in the formation of a well defined lipid corona, whose outer shell is consists of the saturated tails of a hybrid lipid. This cushion softens the membrane perturbation caused by the rough receptor surface and hence makes it more compatible with ordered membrane domains. Interestingly, this favorable solvation by PUFAs seems to be characteristic only for membrane proteins consisting of helical bundles.Our results reveal an unexpected connection between PUFAs and disease: A decrease in the brain PUFA levels might affect GPCR partitioning, thereby compromising their function and perhaps eventually leading to disease. This finding, together with our previous study revealing the role of PUFAs on GPCR oligomerization, highlights the complex interplay of brain membrane lipid composition and neurotransmitter receptor function.

Arachidonic acid in Alzheimer's disease

Alzheimer’s disease is a very complex disease in which neuroinflammation and synaptic dysfunctions play a critical role in association with the two well-known molecular agents of the disease, the Aβ1-42 peptide oligomers and the hyperphosphorylated tau protein. Arachidonic acid, the main member of the ω-6 series, is quantitatively the second polyunsaturated fatty acid in brain and is mainly esterified in membrane phospholipids. It is specifically released by the cytosolic phospholipase A2 whose inhibition or gene suppression counteract the deleterious effects of Aβ1-42 peptide oligomers on cognitive abilities. Arachidonic acid can be reincorporated under the action of the acyl-CoA synthetase 4 and lysophospholipid acyltransferases which remain to be characterized. Free arachidonic acid can be involved in Alzheimer’s disease through several mechanisms. First it is converted by cyclooxygenases-1/2 and the specific prostaglandin synthases into PGE2 and PGD2 which contributes to the occurrence and progression of neuroinflammation. Neuroinflammation has positive as well as negative effects, by favoring Aβ1-42 peptide clearance on one hand and by increasing the production of neurotoxic compounds on the other hand. Second, free arachidonic acid is also involved in synaptic functions as a retrograde messenger and as a regulator of neuromediator exocytosis. Third, some studies indicated that free arachidonic acid and its derivatives activate kinases involved in tau hyperphosphorylation. In addition, the dietary intakes of arachidonic acid in western food increased in the last period. Taken together, these various reports support the hypothesis that arachidonic acid is interesting target in nutrition-based preventive strategies against this disease.

Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture.

Inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in bipolar disorder and in major depressive disorder (MDD). Although the convergence of findings between preclinical and postmortem clinical data is compelling, we investigate why human trials of PUFA as treatment are mixed. We view the biomarker and treatment study findings in light of the evidence for the hypothesis that arachidonic acid hypermetabolism contributes to bipolar disorder pathophysiology and propose that a combined high n-3 plus low n-6 diet should be tested as an adjunct to current medication in future trials.

Enriched dairy fat matrix diet prevents early life lipopolysaccharide-induced spatial memory impairment at adulthood

Polyunsaturated fatty acids (PUFAs) are essential fatty acids, which are critical for brain development and later life cognitive functions. The main brain PUFAs are docosahexaenoic acid (DHA) for the n-3 family and arachidonic acid (ARA) for the n-6 family, which are provided to the post-natal brain by breast milk or infant formula. Recently, the use of dairy lipids (DL) in replacement of vegetable lipids (VL) was revealed to potently promote the accretion of DHA in the developing brain. Brain DHA, in addition to be a key component of brain development, display potent anti-inflammatory activities, which protect the brain from adverse inflammatory events. In this work, we evaluated the protective effect of partial replacement of VL by DL, supplemented or not with DHA and ARA, on post-natal inflammation and its consequence on memory. Mice were fed with diets poor in vegetal n-3 PUFA (Def VL), balanced in vegetal n-3/n-6 PUFA (Bal VL), balanced in dairy lipids (Bal DL) or enriched in DHA and ARA (Supp VL; Supp DL) from the first day of gestation until adulthood. At post-natal day 14 (PND14), pups received a single administration of the endotoxin lipopolysaccharide (LPS) and brain cytokine expression, microglia phenotype and neurogenesis were measured. In a second set of experiments, memory and neurogenesis were measured at adulthood. Overall, our data showed that lipid quality of the diet modulates early life LPS effect on microglia phenotype, brain cytokine expression and neurogenesis at PND14 and memory at adulthood. In particular, Bal DL diet protects from the adverse effect of early life LPS exposure on PND14 neurogenesis and adult spatial memory.