Neuroprotective Actions of Polyunsaturated Fatty Acids with Particular Reference to Alzheimer’s Disease

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are of benefit in Alzheimer’s disease by virtue of their anti-inflammatory actions, ability to modulate neural function, including neurotransmission, membrane fluidity, ion channel, enzyme regulation and gene expression. EPA, DHA, and ω-6 arachidonic acid (AA) form precursors to anti-inflammatory compounds: lipoxins, resolvins, protectins and maresins that suppress leukocyte migration and activation, inhibit NF-κB activation, production of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6, free radical generation, and enhance endothelial nitric oxide generation and augment the healing process. In animal models, the protective action of EPA and DHA against Alzheimer’s disease correlated with increased formation of lipoxins, resolvins, protectins and maresins. EPA, DHA and AA stimulate neurite outgrowth by activating syntaxin 3 that is specifically involved in fast calcium-triggered exocytosis of neurotransmitters. SNAP25 (synaptosomal-associated protein of 25 kDa), a syntaxin partner implicated in neurite outgrowth, interacted with syntaxin 3 only in the presence of AA that allowed the formation of the binary syntaxin 3-SNAP 25 complex. AA stimulated syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion that facilitates neurite outgrowth. These results imply that EPA, DHA, and AA when given in optimal amounts are of benefit in the prevention and treatment of Alzheimer’s disease. PUFAs enhance the concentrations of neurotrophic factors in the brain that may provide additional protection to neurons. Thus, PUFAs by themselves or their stable synthetic analogues could be of benefit in Alzheimer’s disease and other neurodegenerative diseases.

Keywords: Polyunsaturated fatty acids, Alzheimer’s disease, lipoxins, protectins, resolvins, maresins, syntaxin, free radicals, nitric oxide, inflammation, cytokines, tumor necrosis factor.