Norman Salem

Mechanisms of action of docosahexaenoic acid in the nervous system

AbtractThis review describes (from both the animal and human literature) the biological consequences of losses in nervous system docosahexaenoate (DHA). It then concentrates on biological mechanisms that may serve to explain changes in brain and retinal function. Brief consideration is given to actions of DHA as a nonesterified fatty acid and as a docosanoid or other bioactive molecule. The role of DHA-phospholipids in regulating G-protein signaling is presented in the context of studies with rhodopsin. It is clear that the visual pigment responds to the degree of unsaturation of the membrane lipids. At the cell biological level, DHA is shown to have a protective role in a cell culture model of apoptosis in relation to its effects in increasing cellular phosphatidylserine (PS); also, the loss of DHA leads to a loss in PS. Thus, through its effects on PS, DHA may play an important role in the regulation of cell signaling and in cell proliferation. Finally, progress has been made recently in nuclear magnetic responance studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation.

Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimers disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. n-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged alzheimer mouse model

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimers disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. β-Amyloid (Aβ) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Aβ by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Aβ42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Aβ (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both α- and β-APP C-terminal fragment products and full-length APP. BACE1 (β-secretase activity of the β-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against β-amyloid production, accumulation, and potential downstream toxicity.

α-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans.

Blood levels of polyunsaturated fatty acids (PUFA) are considered biomarkers of status. Alpha-linolenic acid, ALA, the plant omega-3, is the dietary precursor for the long-chain omega-3 PUFA eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Studies in normal healthy adults consuming western diets, which are rich in linoleic acid (LA), show that supplemental ALA raises EPA and DPA status in the blood and in breast milk. However, ALA or EPA dietary supplements have little effect on blood or breast milk DHA levels, whereas consumption of preformed DHA is effective in raising blood DHA levels. Addition of ALA to the diets of formula-fed infants does raise DHA, but no level of ALA tested raises DHA to levels achievable with preformed DHA at intakes similar to typical human milk DHA supply. The DHA status of infants and adults consuming preformed DHA in their diets is, on average, greater than that of people who do not consume DHA. With no other changes in diet, improvement of blood DHA status can be achieved with dietary supplements of preformed DHA, but not with supplementation of ALA, EPA, or other precursors.

Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis.

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3- and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy. We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy. Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.

Workshop on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids.

The Workshop on the Essentiality of and Recommended Dietary Intakes (RDIs) for Omega-6 and Omega-3 Fatty Acids was held at The Cloisters, National Institutes of Health (NIH) in Bethesda, Maryland, USA, April 7–9, 1999. The workshop was sponsored by the National Institute on Alcohol Abuse and Alcoholism-NIH, the Office of Dietary Supplements-NIH, The Center for Genetics, Nutrition and Health, and the International Society for the Study of Fatty Acids and Lipids; and cosponsored by several industry groups. The workshop participants consisted of investigators of the role of essential fatty acids in infant nutrition, cardiovascular disease, and mental health. The first two areas were selected because they are the ones where extensive studies involving animal models, clinical intervention trials, and biochemical and physiologic mechanisms and their function have been carried out relative to omega-6 and omega-3 fatty acids. The role of essential fatty acids in mental health is a new, but promising research area. The workshop was truly international in nature bringing together scientists from academia, government, international organizations, and industry, from Australia, Canada, Denmark, France, Italy, Japan, Norway, Switzerland, United Kingdom, and the United States. The first two days of the workshop consisted of presentations and extensive discussions. The format of the workshop was Round Table permitting extensive discussion following individual presentations and at the completion of each session. The first day consisted of Session I. Principles to be Considered in Determining Essentiality and DRIs and Session II. Essential Fatty Acids and Central Nervous System Function. Day two began with Session III. Cardiovascular Disease and ended with Session IV: Relationship of Essential Fatty Acids to Saturated, Monounsaturated, and Trans Fatty Acids. On the morning of the third day, during Session V. Dietary Recommendations and Omega-6:Omega-3 Ratio (LA, LNA, AA, EPA, DHA), industry representatives reported on studies supported by their companies, on clinical interventions, and product development. Representatives from the U.S. Department of Agriculture (USDA), the Pan American Health Organization/World Health Organization (PAHO/WHO) and the Food and Agriculture Organization of the United Nations (FAO) presented their agencies’ scientific studies or policies on the dietary intake of fatty acids, especially essential fatty acids, and their activities in the field. One recommendation deserves explanation here. After much discussion consensus was reached on the importance of reducing the omega-6 polyunsaturated fatty acids (PUFAs) even as the omega-3 PUFAs are increased in the diet of adults and newborns for optimal brain and cardiovascular health and function. This is necessary to reduce adverse effects of excesses of arachidonic acid and its eicosanoid products. Such excesses can occur when too much LA and AA are present in the diet and an adequate supply of dietary omega-3 fatty acids is not available. The adverse effects of too much arachidonic acid and its eicosanoids can be avoided by two interdependent dietary changes. First, the amount of plant oils rich in LA, the parent compound of the omega-6 class, which is converted to AA, needs to be reduced. Second, simultaneously the omega-3 PUFAs need to be increased in the diet. LA can be converted to arachidonic acid and the enzyme, D-6 desaturase, necessary to desaturate it, is the same one necessary to desaturate LNA, the parent compound of the omega-3 class; each competes with the other for this desaturase. The presence of LNA in the diet can inhibit the conversion of the large amounts of LA in the diets of Western industrialized countries which contain too much dietary plant oils rich in omega-6 PUFAs (e.g. corn, safflower, and soybean oils). The increase of LNA, together with EPA and DHA, and reduction of vegetable oils with high

Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline

Docosahexaenoic acid (DHA) plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimers disease. Higher DHA intake is inversely correlated with relative risk of Alzheimers disease. The potential benefits of DHA supplementation in age‐related cognitive decline (ARCD) have not been fully examined.

Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids

Accessible online at: http://BioMedNet.com/karger The Workshop on the Essentiality of and Recommended Dietary Intakes (RDIs) for Omega-6 and Omega-3 Fatty Acids was held at The Cloisters, National Institutes of Health (NIH) in Bethesda, Md., USA, April 7–9, 1999. The workshop was sponsored by the National Institute on Alcohol Abuse and Alcoholism-NIH, the Office of Dietary Supplements-NIH, The Center for Genetics, Nutrition and Health, and the International Society for the Study of Fatty Acids and Lipids, and cosponsored by several industry groups1. The workshop participants consisted of investigators of the role of essential fatty acids in infant nutrition, cardiovascular disease, and mental health. The first two areas were selected because they are the ones where extensive studies involving animal models, clinical intervention trials, and biochemical and

Long Chain Polyunsaturated Fatty Acid Formation in Neonates: Effect of Gestational Age and Intrauterine Growth

The present study was designed to evaluate the effect of gestational age and intrauterine growth on the long chain polyunsaturated fatty acid (LCP) synthesis from dietary precursors in neonates as reflected by plasma pools. These have been considered conditionally essential nutrients for normal growth, sensory maturation, and neurodevelopment. In vivo elongation/desaturation of deuterated d5-linoleic acid (d5-LA) to form arachidonic acid (AA), and d5-α-linolenic acid (d5-LNA) to form docosahexaenoic acid (DHA), was studied in 19 preterm appropriate-for-gestational-age (AGA) infants, 11 AGA term, and 11 intrauterine growth-retarded (IUGR) infants. They received a dose of 50 mg/kg body weight of d5-LA and d5-LNA enterally during the first days of life; d5-labeled derivatized fatty acids were determined in blood samples obtained at 24, 48, and 96 h after dosing. Lipids were extracted and fatty acids analyzed by gas chromatography and negative ion mass spectrometry. Mean concentrations, μg/mL, and d5/d0 for n-3 and n-6 precursor and products were computed at various times and were also integrated over the complete study period. Significantly higher time-integrated concentration of d5-AA and d5-DHA were observed in preterm infants relative to the other two groups. Time-integrated enrichment of DHA relative to LNA was 100-fold lower in preterms, 410-fold lower in term, and 27-fold lower in IUGR infants. Similar significant declines in product to precursor enrichments were noted for the n-6 series. A significant negative correlation of AA and DHA formation based on time-integrated d5/d0 ratios with gestational age was noted; product/precursor enrichment versus gas chromatography for the n-6 series had an r of −0.5, p = 0.001, and for the n-3 series had an r of −0.6, p = 0.0001. Birth weight or weight adequacy did not add further strength to the relationship. We conclude that LCP formation from deuterated precursors occurs as early as 26 wk gestation, and in fact is more active at earlier gestational ages; growth retardation appears to slow down or diminish LCP formation. No quantitative estimates of LCP synthesis or nutritional sufficiency can be derived from these data.

Sirtuin 1 Reduction Parallels the Accumulation of Tau in Alzheimer Disease

Aging and metabolism-related disorders are risk factors for Alzheimer disease (AD). Because sirtuins may increase the life span through regulation of cellular metabolism, we compared the concentration of sirtuin 1 (SIRT1) in the brains of AD patients (n = 19) and controls (n = 22) using Western immunoblots and in situ hybridization. We report a significant reduction of SIRT1 (messenger RNA [mRNA], −29%; protein, −45%) in the parietal cortex of AD patients, but not in the cerebellum. Further analyses in a second cohort of 36 subjects confirmed that cortical SIRT1 was decreased in AD but not in individuals with mild cognitive impairment. SIRT1 mRNA and its translated protein correlated negatively with the duration of symptoms (mRNA, r2 = −0.367; protein, r2 = −0.326) and the accumulation of paired helical filament tau (mRNA, r2 = −0.230; protein, r2 = −0.119), but weakly with insoluble amyloid-&bgr; 42 (mRNA, r2 = −0.090; protein, r2 = −0.072). A significant relationship between SIRT1 levels and global cognition scores proximate to death was also found (r2 = +0.09, p = 0.049). In contrast, cortical SIRT1 levels remained unchanged in a triple-transgenic animal model of AD. Collectively, our results indicate that loss of SIRT1 is closely associated with the accumulation of amyloid-&bgr; and tau in the cerebral cortex of persons with AD.