Brain Docosahexaenoic Acid Research Articles

Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1)

PurposeAlzheimer’s disease (AD) is associated with brain accumulation of amyloid-beta (Aβ) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood–brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA.MethodsThe mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled 3H-oleic acid and 14C-DHA.ResultsFAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of 14C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of 14C-DHA.ConclusionsThese studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.Graphical

Effects of short-term supplementation with DHA-enriched phosphatidylcholine and phosphatidylserine on lipid profiles in the brain and liver of n-3 PUFA-deficient mice in early life after weaning.

Lack of n-3 polyunsaturated fatty acids during the period of maternity drastically lowers the docosahexaenoic acid (DHA) level in the brain of offspring and studies have demonstrated that different molecular forms of DHA are beneficial to brain development. The aim of this study was to investigate the effect of short-term supplementation with DHA-enriched phosphatidylserine (PS) and phosphatidylcholine (PC) on DHA levels in the liver and brain of congenital n-3-deficient mice. Dietary supplementation with DHA significantly changed the fatty acid composition of various phospholipid molecules in the cerebral cortex and liver while DHA-enriched phospholipid was more effective than DHA triglyceride (TG) in increasing brain and liver DHA. Both DHA-PS and DHA-PC could effectively increase the DHA levels, but DHA in the PS form was superior to PC in the contribution of DHA content in the brain ether-linked PC (ePC) and liver lyso-phosphatidylcholine molecular species. DHA-PC showed more significant effects on the increase of DHA in liver TG, PC, ePC, phosphatidylethanolamine (PE) and PE plasmalogen (pPE) molecular species and decreasing the arachidonic acid level in liver PC plasmalogen, ePC, PE and pPE molecular species compared with DHA-PS. The effect of dietary interventions with different molecular forms of DHA for brain and liver lipid profiles is different, which may provide theoretical guidance for dietary supplementation of DHA for people. © 2024 Society of Chemical Industry.

Effect of high-fat diet on the fatty acid profiles of brain in offspring mice exposed to maternal gestational diabetes mellitus.

Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM). Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/β-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot. Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of β-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05). Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM.

Manipulation of Dietary DHA does not Alter DHA Brain Uptake Kinetics in Mice Despite Changing Brain and Plasma DHA Levelsvs

AbstractBackgroundIncreased brain docosahexaenoic acid (DHA) uptake reflects a compensatory mechanism for maintaining brain DHA homeostasis and can be captured through PET‐MRI scan uptake studies using radiolabeled DHA. It has been previously shown that APOE4 status and alcohol intake alter brain DHA uptake in mice. Whether a change in DHA intake affects the brain DHA incorporation coefficient (K*) however is not known.MethodFour‐month‐old C57BL/6J mice were fed either a diet rich in DHA (15 kcal% Fat, 1.7 g/kg ALA, and 7g/kg DHA) or deficient in DHA (15 kcal% Fat and 0.9 mg/kg ALA) for 4 months. At 8 months, anesthetized mice were subjected to dynamic PET‐MRI for 30 min following i.v. injection of 22‐[18F]fluorodocosahexaenoic acid ([18F]FDHA), prepared in‐house through radiosynthesis. Using an image‐derived cardiac input function, brain uptake was assessed by estimating [18F]FDHA K* values using both the Patlak model approach and the irreversible two‐tissue compartmental model (Irr2TCM) with and without correction of the brain radioactivity for radioactive spillover from the skull. Mice were then sacrificed, and the plasma and brains were analyzed using liquid chromatography‐mass spectrometry (LC‐MS) to evaluate differences in the unlabeled concentrations of fatty acids into phospholipids, triglycerides, and other lipids.ResultThere was no significant difference in the [18F]FDHA K* estimates (with either Patlak or Irr2TCM) between mice fed a DHA‐rich or a DHA‐deficient diet. LC‐MS based lipidomic analysis showed that the DHA‐rich diet significantly increased DHA concentration in triglycerides in plasma and in phosphatidylethanolamine in the brain.ConclusionThese results suggest that under physiological conditions, increased dietary intake of DHA in wild‐type mice increases DHA in brain phosphatidylethanolamine and in plasma triglycerides without changing the DHA K*. The net effect likely is increased brain DHA uptake, equal to the product of unesterified DHA plasma concentration and K*. Imaging brain DHA with dynamic [18F]FDHA PET‐MRI is a potentially useful tool not only to investigate the APOE4 phenotype, which promotes DHA dysregulation, but also to assess dietary and pharmacological interventions that affect brain DHA homeostasis as well as to guide future treatments.

The effect of APOEƐ4 on neurocognitive decline is accentuated by female sex and menopause: Identification of mitigating interventions

AbstractBackgroundTwo thirds of those living with AD are female. Age‐standardised AD prevalence is consistently higher at all ages over 70 years in women versus men. The aetiology of the accelerated neurophysiological decline in females is poorly understood. Here we investigate the independent and interactive impact of APOE4 carrier status and menopause.MethodTargeted replacement (APOE3‐TR and APOE4‐TR) rodent models and human cohort studies (European Prevention of Alzheimer’s Dementia (EPAD) and UK Biobank (UKB)) were used to investigate the impact of APOE4, menopause and hormone replacement therapy (HRT) on cognition, brain volumes (assessed by MRI), omega‐3 fatty acid status and synaptic function. In rodents, menopause is elicited by the administration of 4‐vinylcyclohexene diepoxide (VCD), which induces a human‐like “perimenopausal” phenotype, whilst maintaining ovarian tissue integrity.ResultsIn EPAD, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test battery, HRT use in APOE4 only was associated with higher overall cognition and (delayed) memory scores and larger entorhinal and amygdala volumes in APOE4 only. Earlier HRT introduction was associated with larger hippocampal volumes. In UKB, HRT use was associated with improved memory in APOE4/E4. In mice, VCD administration reduced recognition memory, brain docosahexaenoic acid (DHA, omega‐3 fatty acid) levels, and altered synaptic plasticity biomarkers in APOE4‐TR animals, which was mitigated by DHA supplementation (1).ConclusionAn increased penetrance of the APOE4 genotype during the menopausal transition is likely to contribute to the higher incident AD in females, and in APOE4 females versus non‐carriers. HRT and DHA intervention during the menopausal transition, as a critical window of opportunity, may represent effective strategies to support cognitive health into older age in this ‘at‐risk’ (APOE4 female) group, which typically represent 12% of Caucasian populations compared and 33‐50% of AD.1. Pontifex MG et al., FASEB J. 2021 May;35(5):e21583

Choline and Fish Oil Can Improve Memory of Mice through Increasing Brain DHA Level.

Docosahexaenoic acid (DHA) is highly enriched in the brain, and is essential for normal brain development and function. However, evidence suggests that currently used supplements, such as fish oil, do not significantly increase brain DHA levels. Therefore, this study aimed to investigate whether combined fish oil and choline supplementation could affect the type and enrich the content of DHA in the brain. The results revealed that the combined intake of fish oil and choline upregulated the expression of key transporters and receptors, including MFSD2A, FATP1, and FABP5, which increased the uptake of DHA in the brain. Additionally, this supplementation improved the synthesis and release of acetylcholine in the brain, which, in turn, enhanced the learning and memory abilities of mice. These findings suggest that the combined intake of fish oil and choline improves the bioavailability of DHA in the brain.

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

Aging decreases docosahexaenoic acid transport across the blood-brain barrier in C57BL/6J mice.

Nutrients are actively taken up by the brain via various transporters at the blood-brain barrier (BBB). A lack of specific nutrients in the aged brain, including decreased levels of docosahexaenoic acid (DHA), is associated with memory and cognitive dysfunction. To compensate for decreased brain DHA, orally supplied DHA must be transported from the circulating blood to the brain across the BBB through transport carriers, including major facilitator superfamily domain-containing protein 2a (MFSD2A) and fatty acid-binding protein 5 (FABP5) that transport esterified and non-esterified DHA, respectively. Although it is known that the integrity of the BBB is altered during aging, the impact of aging on DHA transport across the BBB has not been fully elucidated. We used 2-, 8-, 12-, and 24-month-old male C57BL/6 mice to evaluate brain uptake of [14C]DHA, as the non-esterified form, using an in situ transcardiac brain perfusion technique. Primary culture of rat brain endothelial cells (RBECs) was used to evaluate the effect of siRNA-mediated MFSD2A knockdown on cellular uptake of [14C]DHA. We observed that the 12- and 24-month-old mice exhibited significant reductions in brain uptake of [14C]DHA and decreased MFSD2A protein expression in the brain microvasculature compared with that of the 2-month-old mice; nevertheless, FABP5 protein expression was up-regulated with age. Brain uptake of [14C]DHA was inhibited by excess unlabeled DHA in 2-month-old mice. Transfection of MFSD2A siRNA into RBECs decreased the MFSD2A protein expression levels by 30% and reduced cellular uptake of [14C]DHA by 20%. These results suggest that MFSD2A is involved in non-esterified DHA transport at the BBB. Therefore, the decreased DHA transport across the BBB that occurs with aging could be due to age-related down-regulation of MFSD2A rather than FABP5.

APOE e4 dependent deficits in brain DHA phospholipids and mfsd2a in Alzheimer’s disease patients with severe cerebral amyloid angiopathy

AbstractBackgroundThe apolipoprotein E e4 allele (APOE4) is a major risk factor, contributing to vascular pathologies in AD which include CAA, BBB dysfunction and reduced cerebral vascular integrity. The diminished capacity of APOE4 to transport docosahexaenoic acid (DHA), an essential fatty acid required for the structural and functional maintenance and vascular integrity of the brain, could also contribute to AD pathogenesis. However, it remains undetermined if changes in the brain DHA content of phospholipids (PL) and DHA transporters exist in relation to APOE4, AD diagnosis and CAA pathology.MethodWe performed liquid chromatography/mass spectrometry‐based PL analysis of the cerebrovascular and parenchymal fractions from autopsied human brain of pathologically confirmed AD cases and controls. We performed an antibody‐based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects and brain homogenates from transgenic mice with human APOE (APOE‐TR) and APOE‐TR crossed with mice with five AD mutations (EFAD). We performed proteomic analyses of the cerebrovascular and parenchymal fractions of the brains from 50‐week‐old APOE‐TR.ResultIn the cerebrovasculature and parenchyma, DHA containing PL species were lower in ε4 carriers with AD compared to control ε4 carriers. We observed an ε4‐dependent decrease in mfsd2a level in the cerebrovasculature of ε4 carriers compared to non‐carriers. Stratification of DHA containing PL by CAA showed that these PL levels were reduced in ε4 positive AD patients with severe CAA. In addition, brain levels of DHA containing PC species and mfsd2a were lower in APOE4‐TR and E4FAD mice compared to other genotypes in each mouse model. Furthermore, protein levels of glucose transporter 1 (Glut1) and a metabolite transporter, monocarboxylate transporter 1 (MCT1), were lower in the cerebrovasculature of APOE4‐TR relative to APOE3‐TR and APOE2‐TR mice.ConclusionThese findings demonstrate that brain DHA deficiencies in ε4 carriers may be due to reduced mfsd2a expression and partly associated with severe CAA. Thus, targeting this transport mechanism may improve the bioavailability of DHA into the brains of ε4 carriers who are at risk of developing AD.

Inhibition of cPLA2 ameliorates memory deficits and reduces neuroinflammation in ApoE4‐TR mice

AbstractBackgroundThe activation of calcium‐dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling by promoting the conversion of arachidonic acid (AA) into eicosanoids, while catabolizing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We previously found higher cPLA2 activation correlated with increased pro‐inflammatory lipid metabolites in APOE4 brains. However, it is not known whether the inhibition cPLA2 will decrease neuroinflammation ApoE4‐mice.MethodFirst, ApoE4 targeted replacement mice (ApoE4‐TR, n = 3, male, 4 months old) were treated daily with vehicle or the specific cPLA2 inhibitor ASB14780 (10 mg/kg, intraperitoneal) for three days. The brains were collected and analyzed using LC‐MS based lipidomics. Second, ApoE2‐TR (n = 14, 8M/6F), ApoE3‐TR (n = 12, 5M/7F) and ApoE4‐TR (n = 17, 8M/9F) mice were fed a low‐DHA diet starting at 6 months old. ApoE4 mice were treated daily for three weeks with vehicle (n = 8, 4M/4F) or 10mg/kg/day ASB14780 IP (n = 9, 5M/4F) starting at 14 months old. Behavioral tests were subsequently conducted on the mice, after which the brains were collected for lipidomic and biochemical analyses.ResultIP ASB14780 was detected in brain tissue corresponding with decreases in pro‐inflammatory metabolites of AA after only 3 days treatment in ApoE4‐TR mice. In addition, long term ASB14780 treatment decreased brain cPLA2 phosphorylation levels and significantly increased brain EPA and DHA levels (p&lt;0.01 for both) but did not change brain AA levels in ApoE4‐TR mice. Compared to ApoE3‐TR mice, untreated ApoE4‐TR mice had higher levels of inflammatory eicosanoids (e.g., prostaglandin E2, PGE2) resulting from AA metabolism. However, ASB14780 treatment decreased inflammatory metabolites in ApoE4‐TR mice. Additionally, ASB14780‐treatment was able to reduce microglia activation in ApoE4‐TR mice (p = 0.04 for hippocampus and p&lt;0.01 for cortex). For behavioral experiments, ApoE4‐TR mice had significantly lower discrimination index compared to ApoE3‐TR mice at 15 months using the novel object recognition test (p = 0.029). Treatment with ASB14780 ameliorated the recognition deficits of ApoE4‐TR mice but the effects did not reach statistical significance (p = 0.15).ConclusionOur findings reveal inhibition of cPLA2 with ASB14780 could ameliorate eicosanoid‐driven neuroinflammation in ApoE4 mice, restoring synaptic dysfunction, and preventing behavioral deficits. cPLA2 represents a potential drug target to mitigate increased neuroinflammation with APOE4 and AD.

Milk fat globule membrane plus milk fat increase docosahexaenoic acid availability in infant formulas

PurposeMilk fat globule membrane (MFGM) has components with emulsifier properties that could affect the provision of substrates to the brain. We evaluated the effects of MFGM plus milk fat addition to infant formulas on docosahexaenoic acid (DHA) availability and gut development.MethodsIn Experiment 1, suckling piglets were divided into 3 groups: Group L1 (n = 8): fed with a vegetal fat formula with palm oil; L2 (n = 8): canola oil formula and L3 (n = 8): milk fat + canola oil + 1% Lacprodan (3% MFGM of total protein content). In Experiment 2, Group L4 (n = 7): fed with canola oil + 1% Lacprodan (3% MFGM) and Group L5 (n = 5): milk fat + canola oil + 2% Lacprodan (6% MFGM). All formulas contained 0.2% DHA and 0.2% arachidonic acid.ResultsIn Experiment 1, DHA was similar among the groups in both total fatty acids and plasma phospholipids (PL). However, 3% MFGM (L3) increased significantly the proportion of DHA and LC-PUFA n-3 in liver total fatty acids, jejunum, and also in jejunum PL respect to the other formulas. There were no changes in gut histology, cell proliferation, apoptosis, or brain DHA content. In Experiment 2, higher MFGM dose was used. Then, higher DHA was not only found in peripheral tissues of 6% MFGM (L5) piglets but also in plasma PL, while a similar trend was observed in cortex PL (p = 0.123).ConclusionIn conclusion, MFGM plus milk fat may increase DHA availability of infant formulas which could contribute to their beneficial health effects.

Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights.

Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases.

Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer's Disease.

Polyunsaturated fatty acids (PUFAs) are a class of fatty acids that are closely associated with the development and function of the brain. The most abundant PUFA is docosahexaenoic acid (DHA, 22:6 n-3). In humans, low plasmatic concentrations of DHA have been associated with impaired cognitive function, low hippocampal volumes, and increased amyloid deposition in the brain. Several studies have reported reduced brain DHA concentrations in Alzheimer’s disease (AD) patients’ brains. Although a number of epidemiological studies suggest that dietary DHA consumption may protect the elderly from developing cognitive impairment or dementia including AD, several review articles report an inconclusive association between omega-3 PUFAs intake and cognitive decline. The source of these inconsistencies might be because DHA is highly oxidizable and its accessibility to the brain is limited by the blood–brain barrier. Thus, there is a pressing need for new strategies to improve DHA brain supply. In the present study, we show for the first time that the intranasal administration of nanovectorized DHA reduces Tau phosphorylation and restores cognitive functions in two complementary murine models of AD. These results pave the way for the development of a new approach to target the brain with DHA for the prevention or treatment of this devastating disease.

Emerging Role of Phospholipids and Lysophospholipids for Improving Brain Docosahexaenoic Acid as Potential Preventive and Therapeutic Strategies for Neurological Diseases.

Docosahexaenoic acid (DHA, 22:6n-3) is an omega-3 polyunsaturated fatty acid (PUFA) essential for neural development, learning, and vision. Although DHA can be provided to humans through nutrition and synthesized in vivo from its precursor alpha-linolenic acid (ALA, 18:3n-3), deficiencies in cerebral DHA level were associated with neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases. The aim of this review was to develop a complete understanding of previous and current approaches and suggest future approaches to target the brain with DHA in different lipids’ forms for potential prevention and treatment of neurodegenerative diseases. Since glycerophospholipids (GPs) play a crucial role in DHA transport to the brain, we explored their biosynthesis and remodeling pathways with a focus on cerebral PUFA remodeling. Following this, we discussed the brain content and biological properties of phospholipids (PLs) and Lyso-PLs with omega-3 PUFA focusing on DHA’s beneficial effects in healthy conditions and brain disorders. We emphasized the cerebral accretion of DHA when esterified at sn-2 position of PLs and Lyso-PLs. Finally, we highlighted the importance of DHA-rich Lyso-PLs’ development for pharmaceutical applications since most commercially available DHA formulations are in the form of PLs or triglycerides, which are not the preferred transporter of DHA to the brain.

Entorhinal thickness: A marker of DHA supplementation efficacy?

AbstractBackgroundThe entorhinal cortex (ERC) area in the brain is affected early in AD, particularly among APOE4 carriers. We previously reported a positive association between plasma phospholipid docosahexaenoic acid (DHA) levels and the ERC thickness in the Aging Brain Program. We hypothesize that increases in plasma DHA after high‐dose DHA supplementation protects against thinning of the ERC when started before cognitive impairment including in APOE4 carriers, and that ERC thickness can be a useful marker for DHA supplementation efficacy.MethodWe examined the effect of DHA treatment and association of plasma DHA species on the changes in the ERC area in the DHA Brain Delivery Pilot Trial (NCT02541929). T1‐weighted MRI scans were collected at 3T and FreeSurfer software was used to segment the ERC thickness. Total DHA, DHA in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and phosphatidylethanolamine (PE) were measured in plasma together with Red blood cell (RBC) DHA levels before and after randomization to 2 grams of triglyceride DHA per day vs placebo over 6 months (n=28). Participants were all cognitively normal, consumed less than 200 mg of DHA per day, and were stratified by APOE4 genotype before randomization.ResultDHA treatment, adjusted for APOE4, was associated with a significant increase in ERC area thickness compared with placebo (mean group difference in ERC change (95% CI) 0.161 (0.003, 0.319), p=0.046). Among DHA subspecies measured, greater increase in plasma PC DHA levels after supplementation was significantly correlated with greater ERC area (mean ERC change per SD of PC DHA=0.103, p=0.011). The association persisted after adjusting for APOE4 status (mean ERC change per SD of PC DHA=0.109, p=0.007), indicating that the effect was independent of APOE4 status.ConclusionThese preliminary findings support a protective effect of high dose DHA in preserving the ERC thickness, including among APOE4 carriers. This finding supports early intervention, before the onset of cognitive impairment, with high dose DHA supplementation in individuals at risk of cognitive decline. PREVENTE4 trial (NCT03613844) is ongoing to help understand whether high dose DHA can prevent cognitive decline in individuals at increased risk of AD.HNY is supported by AA NIRG‐15‐361854, R01AG054434, R21AG056518, ADDF GC‐201711‐2014197.

Effects of plant-based versus marine-based omega-3 fatty acids and sucrose on brain and liver fatty acids in a mouse model of chemotherapy

ABSTRACT Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Why Have the Benefits of DHA Not Been Borne Out in the Treatment and Prevention of Alzheimer's Disease? A Narrative Review Focused on DHA Metabolism and Adipose Tissue.

Docosahexaenoic acid (DHA), an omega-3 fatty acid rich in seafood, is linked to Alzheimer’s Disease via strong epidemiological and pre-clinical evidence, yet fish oil or other DHA supplementation has not consistently shown benefit to the prevention or treatment of Alzheimer’s Disease. Furthermore, autopsy studies of Alzheimer’s Disease brain show variable DHA status, demonstrating that the relationship between DHA and neurodegeneration is complex and not fully understood. Recently, it has been suggested that the forms of DHA in the diet and plasma have specific metabolic fates that may affect brain uptake; however, the effect of DHA form on brain uptake is less pronounced in studies of longer duration. One major confounder of studies relating dietary DHA and Alzheimer’s Disease may be that adipose tissue acts as a long-term depot of DHA for the brain, but this is poorly understood in the context of neurodegeneration. Future work is required to develop biomarkers of brain DHA and better understand DHA-based therapies in the setting of altered brain DHA uptake to help determine whether brain DHA should remain an important target in the prevention of Alzheimer’s Disease.

LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4.

Compared with APOE3, APOE4 is associated with greater age-related cognitive decline and higher risk of neurodegenerative disorders. Therefore, development of supplements that target APOE genotype-modulated processes could provide a great benefit for the aging population. Evidence suggests a link between APOE genotype and docosahexaenoic acid (DHA); however, clinical studies with current DHA supplements have produced negative results in dementia. The lack of beneficial effects with current DHA supplements may be related to limited bioavailability, as the optimal form of DHA for brain uptake is lysophosphatidylcholine (LPC)-DHA. We previously developed a method to enrich the LPC-DHA content of krill oil through lipase treatment (LT-krill oil), which resulted in fivefold higher enrichment in brain DHA levels in wild-type mice compared with untreated krill oil. Here, we evaluated the effect of a control diet, diet containing krill oil, or a diet containing LT-krill oil in APOE3- and APOE4-targeted replacement mice (APOE-TR mice; treated from 4 to 12 months of age). We found that DHA levels in the plasma and hippocampus are lower in APOE4-TR mice and that LT-krill oil increased DHA levels in the plasma and hippocampus of both APOE3- and APOE4-TR mice. In APOE4-TR mice, LT-krill oil treatment resulted in higher levels of the synaptic vesicle protein SV2A and improved performance on the novel object recognition test. In conclusion, our data demonstrate that LPC-DHA/EPA-enriched krill oil can increase brain DHA and improve memory-relevant behavior in mice that express APOE4. Therefore, long-term use of LT-krill oil supplements may on some level protect against age-related neurodegeneration.

Potential role of hepatic lipase in the accretion of docosahexaenoic acid (DHA) by the brain

DHA (docosahexaenoic acid) is an essential fatty acid that is required for the normal development and function of the brain. Because of its inability to synthesize adequate amounts of DHA from the precursors, the brain has to acquire DHA from plasma through the blood brain barrier (BBB). Recent studies demonstrated the presence of a transporter at the BBB that specifically transports DHA into the brain in the form of lysophosphatidylcholine (LPC-DHA). However, the mechanism by which LPC-DHA is generated in the plasma is not known. Our previous studies showed that there are at least three different enzymes - lecithin cholesterol acyltransferase (LCAT), endothelial lipase (EL), and hepatic lipase (HL), which can generate LPC-DHA from sn-2 DHA phosphatidylcholine. Here we determined the relative contributions of these enzymes in the delivery of DHA to the brain by measuring the brain DHA levels in the mice deficient in each of these enzymes. The results show that the brain DHA levels of LCAT-deficient mice or EL-deficient mice were not significantly lower than those of their littermates. However, brain DHA was significantly decreased in HL deficient mice (13.5% of total fatty acids) compared to their littermates (17.1%) (p < 0.002), and further decreased to 8.3% of total fatty acids in mice deficient in both HL and EL. These results suggest that HL activity may be the major source for the generation of LPC-DHA in the plasma necessary for transport into the brain, and EL might contribute to this process in the absence of HL.