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Bad Breakdown: How Essential Fatty Acids Put Up With Free Radicals

Omega-3 and omega-6 fatty acids play an important, yet complicated, role in brain growth and disease, more and more research is showing. These are the same “essential” fats touted in ads for everything from baby formula to supplements to protein bars. They’re essential because the body needs them for maintaining healthy cells, especially for brain and nerve function, but humans can’t produce them. The only source is through what humans eat. 

“We know that omega-3s concentrate in the brain, and if infants are not given enough of them, their brains will not develop properly,” said Paul Axelsen, MD, a professor in the departments of Pharmacology, Medicine, and Biochemistry & Biophysics, who recently published a study that looked at their companion role in the brain in ACS Chemical Neuroscience. “But we haven’t the foggiest idea of their function. We know far more about omega-6s,” he said. For example, aspirin, acetaminophen, and ibuprofen all work by inhibiting omega-6 metabolism, but these anti-inflammatories don’t interfere with omega-3 breakdown.

“This paper’s findings are the biggest clue yet as to the function of omega-3s,” he added.

Omega-6s are derived from many different kinds of plant and animal products. Omega-3s come primarily from fatty fish, such as salmon, mackerel, and tuna, and, to a lesser extent, walnuts and flaxseed, but they are not as broadly available in the natural human diet as omega-6s. Both are polyunsaturated fatty acids, but they differ slightly from each other in their chemical structure.

Researchers are particularly interested in the fatty acids because of their role in neurodegeneration, specifically Alzheimer’s disease (AD). Oxidative stress -- an imbalance between free radicals (highly reactive uncharged molecules) and the body’s ability to counteract their harm -- is frequently seen in Alzheimer’s patients, but its pathological significance is not well understood. What is known, though, is that AD amyloid plaques can also form complexes with metal ions, such as copper, and form free radicals.

With fatty acids abundant in the brain, and especially vulnerable to free-radical attack, their degradation can lead to some nasty products. Several of these are known to be elevated in AD patients and have been implicated in causing the death of brain cells.

To get a better understanding of fatty acid metabolism in the brain, Axelsen’s team radio-labeled omega-6s and injected them into AD and normal mice. The injected omega-6s entered the brain and were subject mainly to free-radical attack. In addition, the extent of the attack was greater in the hippocampus of AD mice, where amyloid plaques are abundant.

Fatty acids are broken down either by enzymes or free radicals. When enzymes are involved, the body takes some degree of control over the process. When free radicals are involved, however, Axelsen calls it a “wild west shootout - free radicals just go around and shoot up everything.” This means, of course, that free radicals make no distinction when attacking omega-3s and omega-6s.

When the team found that omega-6s are mainly broken down by free radicals in normal mice and that they are broken down more near amyloid plaques in AD mice, it became clear that Alzheimer’s amyloid plaques are not quiescent, as once thought. Quite to the contrary, they are highly active areas of free-radical damage close to nerve cells.

The “capstone” of the paper, as Axelsen puts it, is that there must be an important role for omega-3s in the brain. “Omega-3s may be a sponge for free-radicals, preventing them from attacking omega-6s, which are essential for life,” he says. A function like this may explain why there are so many omega-3s found in the brain.

This work, although still very fundamental in nature, immediately suggests therapeutic possibilities in AD. “It’s premature to make any dietary recommendations at this point, but we’re certainly thinking along that way,” allows Axelsen. The team is now working with labeled omega-3s to find out more about these essential, but mysterious molecules.

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