Counting the praises of omega-3: (left to right) Drake Mitchell, NIAAA; panel chair Norman Salem, NIAAA; Stanley Rapoport, NIA; and John Paul SanGiovanni, NEI

Diets low in omega-3 fatty acids—especially the highly unsaturated docosahexaenoic (DHA)—take their toll on cell signaling, vision, and cognition.

These effects are clearly demonstrated in rat studies and in studies involving patients with Alzheimer’s disease and age-related macular degeneration (AMD), panelists reported at a Research Festival symposium on "Regulation of Nervous System Structure and Function by Dietary Polyunsaturated Fatty Acids."

The absence of omega-3 fatty acids from the diet results in the replacement of DHA by docosapentaenoic acid (DPA) omega-6, observed Norman Salem, Jr., chief of the Laboratory of Membrane Biochemistry & Biophysics, NIAAA, and of the Section on Nutritional Neuroscience.

"They’re both long-chained and they’re both PUFAs [polyunsaturated fatty acids], but there is a difference in structure at the atomic level that causes major physiologic differences. It’s one of the most amazing things I’ve ever seen in biology—and that’s why I’ve been working on this for decades."

That one structural difference manifests itself in olfactory deficits, an inability to remember an escape route, and neuroanatomical defects such as decreased neuron size and density and impaired dendritic tree development in the DHA-deprived cohort of rats fed otherwise-identical diets.

The bottom-line explanation for these findings, "we think," Salem said, is disrupted regulation of G protein–coupled receptor signaling (GPCR).

Drake Mitchell, acting chief of the Section on Fluorescence Studies, bolstered the GPCR signaling hypothesis with his report on a series of rat studies in which the replacement of omega-3 PUFA with omega-6 PUFA disrupted regulation of GPCR signaling, membrane composition, and visual responses in the retina.

Human retinal health and disease, said John Paul SanGiovanni, staff scientist in the Clinical Trials Branch, NEI, and project officer of the Age-Related Eye Disease Study 2 (AREDS2), are intimately connected to the level of dietary intake of long-chain PUFAs, specifically the omega-3 fatty acids DHA and EPA (eicosapentaenoic acid).

Findings from NEI’s first AREDS trial and other studies examining the relationship of dietary omega-3 long-chain PUFA and the likelihood of having the neovascular form of AMD, which accounts for most AMD-related vision loss, SanGiovanni said, are "consistent"—decreasing risk with increasing intake.

In the NEI study, involving 658 participants with neovascular AMD and 1,080 AMD-free healthy control subjects, those consuming the highest amounts of DHA had a 50 percent decreased risk of having neovascular AMD relative to peers reporting the lowest levels of DHA intake. Other NEI findings include a protective effect of EPA on progression to central geographic atrophy and vision loss, and a synergistic protective effect of aspirin with either DHA or EPA on prevalence and incidence of sight-threatening AMD.

A newly launched phase III clinical trial—AREDS2—will enroll 4,000 AMD patients and assess the value of dietary DHA and EPA in addition to the antioxidant regimen tested in the earlier AREDS trial, SanGiovanni noted.

Brain AA findings in a rat model of neuroinflammation—elevated AA release from and reincorporation into brain phospholipids and increased brain activity in phospholipase A2 in rats subjected to lipopolysaccharide infusion—provided a basis for ongoing studies in patients with Alzheimer’s disease and healthy control subjects.

Stanley Rapoport, chief of the Brain Physiology and Metabolism Section, NIA, reported PET imaging data on increased incorporation of intravenously injected radiolabeled AA from plasma into the brain regions of Alzheimer’s disease patients where brain blood flow was reduced.

Related findings include the fact that lithium and other agents used to treat bipolar disorder decrease AA turnover in rat brain phospholipids, as well as brain phospholipase A2 activity, Rapoport said. He noted that increased AA incorporation from plasma on PET may be used as a marker of neuroinflammation in Alzheimer’s disease and conditions such as AIDS dementia and multiple sclerosis.

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