Background Dietary n-3 polyunsaturated fatty acids improve brain functioning in animal studies, but there is limited study of whether this type of fat protects against Alzheimer disease. Objective To examine whether fish consumption and intake of different types of n-3 fatty acids protect against Alzheimer disease. Design Prospective study conducted from 1993 through 2000, of a stratified random sample from a geographically defined community. Participants were followed up for an average of 3.9 years for the development of Alzheimer disease. Patients A total of 815 residents, aged 65 to 94 years, who were initially unaffected by Alzheimer disease and completed a dietary questionnaire on average 2.3 years before clinical evaluation of incident disease. Main Outcome Measure Incident Alzheimer disease diagnosed in a structured neurologic examination by means of standardized criteria. Results A total of 131 sample participants developed Alzheimer disease. Participants who consumed fish once per week or more had 60% less risk of Alzheimer disease compared with those who rarely or never ate fish (relative risk, 0.4; 95% confidence interval, 0.2-0.9) in a model adjusted for age and other risk factors. Total intake of n-3 polyunsaturated fatty acids was associated with reduced risk of Alzheimer disease, as was intake of docosahexaenoic acid (22:6n-3). Eicosapentaenoic acid (20:5n-3) was not associated with Alzheimer disease. The associations remained unchanged with additional adjustment for intakes of other dietary fats and of vitamin E and for cardiovascular conditions. Conclusion Dietary intake of n-3 fatty acids and weekly consumption of fish may reduce the risk of incident Alzheimer disease.

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Consumption of Fish and n-3 Fatty Acids and Risk of Incident Alzheimer Disease

▪ Abstract Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Degree of unsaturation of fatty acids affects physical properties of membrane phospholipids and stored triglycerides. In addition, metabolites of polyunsaturated fatty acids are used as signaling molecules in many organisms. Three desaturases, Δ9, Δ6, and Δ5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Δ9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Δ5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in plants and fish, the primary role of HUFAs in mammals is cell signaling. Arachidonic acid is required as substrates...

Structure, function, and dietary regulation of δ6, δ5, and δ9 desaturases

This 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 resonance studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation.

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Mechanisms of action of docosahexaenoic acid in the nervous system

The (n-3) fatty acids are essential dietary nutrients, and one of their important roles is providing docosahexaenoic acid [22:6(n-3)] (DHA) for growth and function of nervous tissue. Reduced DHA is associated with impairments in cognitive and behavioral performance, effects which are particularly important during brain development. Recent studies suggest that DHA functions in neurogenesis, neurotransmission, and protection against oxidative stress. These functions relate to the roles of DHA within the hydrophobic core of neural membranes and effects of unesterified DHA. Reviewed here are some of the recent studies that have begun to elucidate the role of DHA in brain development and function. A better understanding of development and age-specific changes in DHA transfer and function in the developing brain may provide important insight into the role of DHA in developmental disorders in infants and children, as well as at other stages of the lifespan.

Dietary (n-3) Fatty Acids and Brain Development

Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and c...

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Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels

Recent evidence indicates that long-chain polyunsaturated fatty acids (PUFAs) can prevent cardiac arrhythmias by a reduction of cardiomyocyte excitability. This was shown to be due to a modulation of the voltage-dependent inactivation of both sodium (INa) and calcium (ICa) currents. To establish whether PUFAs also regulate neuronal excitability, the effects of PUFAs on INa and ICa were assessed in CA1 neurons freshly isolated from the rat hippocampus. Extracellular application of PUFAs produced a concentration-dependent shift of the voltage dependence of inactivation of both INa and ICa to more hyperpolarized potentials. Consequently, they accelerated the inactivation and retarded the recovery from inactivation. The EC50 for the shift of the INa steady-state inactivation curve was 2.1 +/- 0.4 microM for docosahexaenoic acid (DHA) and 4 +/- 0.4 microM for eicosapentaenoic acid (EPA). The EC50 for the shift on the ICa inactivation curve was 2.1 +/- 0.4 for DHA and > 15 microM for EPA. Additionally, DHA and EPA suppressed both INa and ICa amplitude at concentrations > 10 microM. PUFAs did not affect the voltage dependence of activation. The monounsaturated oleic acid and the saturated palmitic acid were virtually ineffective. The combined effects of the PUFAs on INa and ICa may reduce neuronal excitability and may exert anticonvulsive effects in vivo.

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Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons

Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model

In this study a pharmacokinetic-pharmacodynamic model is proposed for drugs with nonlinear elimination kinetics. We applied such an integrated approach to characterize the pharmacokinetic-pharmacodynamic relationship of phenytoin. In parallel, the anticonvulsant effect and the electroencephalogram (EEG) effect were used to determine the pharmacodynamics. Male Wistar-derived rats received a single intravenous dose of 40 mg · kg−1 phenytoin. The increase in the threshold for generalized seizure activity (TGS) was used as the anticonvulsant effect and the increase in the total number of waves in the 11.5 to 30 Hz frequency band was taken as the EEG effect measure. Phenytoin pharmacokinetics was described by a saturation kinetics model with Michaelis-Menten elimination. V max and K mvalues were, respectively, 386 ± 31 μg · min−1and 15.4 ± 2.2 μg · ml−1 for the anticonvulsant effect in the cortical stimulation model and 272 ± 31 μg · min−1 and 5.9 ± 0.7 μg · ml−1 for the EEG effect. In both groups, a delay to the onset of the effect was observed relative to plasma concentrations. The relationship between phenytoin plasma concentrations and effect site was estimated by an equilibration kinetics routine, yielding mean k e0 values of 0.108 and 0.077 min−1 for the anticonvulsant and EEG effects, respectively. The EEG changes in the total number of waves could be fitted by the sigmoid E max model, but E max values could not be estimated for the nonlinear relationship between concentration and the increase in TGS. An exponential equation ( E = E + B n  ·  C n ) derived from the sigmoid E max model was applied to describe the concentration-anticonvulsant effect relationship, under the assumption that E maxvalues cannot be reached within acceptable electric stimulation levels. This approach yielded a coefficient ( B ) of 2.0 ± 0.4 μA · ml · μg−1 and an exponent ( n ) of 2.7 ± 0.9. The derived EC50value of 12.5 ± 1.3 μg · ml−1 for the EEG effect coincides with the “therapeutic range” in humans.

R.A. Voskuyl

Papers

Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons

Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model

Pharmacokinetic-Pharmacodynamic Modeling of the Anticonvulsant and Electroencephalogram Effects of Phenytoin in Rats

Seizure patterns in kindling and cortical stimulation models of experimental epilepsy

Excitability increase of neurons in olfactory cortex slices of the guinea pig after penicillin administration