Docosahexaenoic acid (DHA)—the stuff that allegedly gives brain- boosting power to fish oil and baby formula—enhances neurogenesis and neurite outgrowth in transgenic mice with naturally elevated levels of the compound, according to a study in the June 22 PNAS Early Edition. The mice also showed modest gains in spatial learning performance, compared to wild-type animals. “Some papers have reported [DHA’s] effects on behavior, and others have reported its effects on neuronal regeneration,” said senior investigator Jing Kang, Massachusetts General Hospital, Boston, in an interview with ARF. “Now we link the two. The [neuroregenerative] effects may be a mechanism responsible for the improved behavioral performance,” he said.

The transgenic mice in the new study have higher endogenous DHA levels because they express a roundworm gene, Fat-1, that enables them to produce omega-3 fatty acids from the omega-6 type. DHA is an omega-3 polyunsaturated fatty acid (PUFA) that helps preserve post-synaptic membranes (Calon et al., 2004 and ARF related news story). The compound appeared to offer some benefit to people with mild Alzheimer disease in at least one clinical trial (Freund-Levi et al., 2006 and ARF related news story), and diets rich in omega-3 PUFAs have been linked to reduced AD risk in epidemiological studies (see, e.g., Morris et al., 2003 and ARF related news story).

To investigate mechanisms underlying DHA’s effects on cognition, first author Chengwei He and colleagues analyzed Fat-1 mice because they believed doing so would eliminate confounding effects of manipulating DHA levels through diet. Using the cell division marker bromodeoxyuridine (BrdU) to mark newborn neurons, the researchers saw evidence of increased neurogenesis in the dentate gyrus of Fat-1 mice, relative to wild-type animals. Furthermore, Golgi-Cox staining revealed increased dendritic spine density in CA1 pyramidal neurons of the Fat-1 mice. And sure enough, these animals also outperformed their wild-type counterparts in the Morris water maze, a commonly used rodent spatial learning test.

The observations of increased neurogenesis and neurite outgrowth in Fat-1 mice drew support from a set of in vitro experiments the authors did to examine DHA’s effect on neurite outgrowth in a more carefully controlled system. They found that DHA treatment increased neuronal proliferation, neurite length, neurite number, and number of neuritic branches in cultured cells undergoing neuronal differentiation from an embryonic stem cell line (G-olig2).

While the authors contend that the Fat-1 mouse eliminates confounding effects of dietary manipulation to elevate DHA intake, some scientists point out that the observed effects on neuroregeneration could also stem from other variations in the mouse model. Robert Friedland, of the University of Louisville, Kentucky, noted that Fat-1 mice have decreased levels of n-6 fatty acids and changes in inflammatory genes and proteins (Ménesi et al., 2009).

It is also hard to determine whether mouse neurogenesis studies would be relevant to people with AD, especially when the regions exhibiting neurogenesis in mice (e.g., subventricular zones, dentate gyrus) differ from those showing neuron loss in AD patients (e.g., CA1, entorhinal layer 2), suggested Greg Cole of the University of California, Los Angeles, in an e-mail to ARF (see full comment below). “Nevertheless, it is hard to believe that increasing adult neurogenic potential would have no utility in a disease like AD, which has neurodegeneration in many different systems,” wrote Cole, author of an in-press review on omega-3 fatty acids and dementia (Cole et al., 2009).—Esther Landhuis

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  1. There are not that many transgenes that improve cognitive function over baseline, so it is always interesting when that happens, as with this report from the Kang lab on Fat-1 transgenics that synthesize DHA from Fat-1, resulting in elevated brain DHA, increased neurogenesis, dendritic spines, synaptic markers, and improved water maze memory. DHA enhances developmental neurogenesis, and lots of data show increased neuritogenesis in various systems, in keeping with the equivalent of a trophic activity. The increase in dendritic spines in CA1 is pretty consistent with the types of things that our group and others have seen, and this paper shows this is likely a direct effect of DHA. DHA is clearly pleiotropic, and multiple effects that might benefit an aging brain have been reported with dietary DHA, including elevating neurogenesis, increasing BDNF, increasing Akt activity, and elevating production of neuroprotectin D1—to name a few. It is hard to know how studies on mouse neurogenesis translate to humans or diseased patients with region-specific neuron loss that is generally not in the regions where people see neurogenesis (subventricular zones, dentate gyrus). In addition, there is no clear evidence for anything going on in these mice in regions where there are problems with neuron loss in AD—such as the CA1, entorhinal layer 2, or subcortical cholinergic and other systems. Nevertheless, it is hard to believe that increasing adult neurogenic potential would have no utility in a disease like AD, which has neurodegeneration in many different systems.

    Increasing DHA in the diet can suppress several aspects of AD pathogenesis in mouse models where it has many pleiotropic effects. For example, it can reduce brain arachidonic acid (AA) and AA metabolites, and some of these may be playing a deleterious role. For example, the AA metabolites from cyclooxygenases are blocked by non-steroidal anti-inflammatory drugs (NSAIDs), which can also slow Aβ accumulation, be neuroprotective, or help correct LTP and cognitive deficits. Further, Lennart Mucke’s lab has shown that AA release by a specific phospholipase A2 is elevated in AD and AD mouse models, and that selectively suppressing this elevated cPLA2 with a genetic knockout corrects cognitive deficits. The most mechanistically interesting thing about elevating DHA levels with the Fat-1 transgene rather than by dietary manipulation is that it raises DHA levels without lowering AA, and therefore isolates some of the benefits of DHA (while presumably losing those due to effects on AA). Despite some minor issues, this paper is useful in isolating some of the direct effects of dietary DHA, and it will be interesting to see what impact Fat-1 transgenes have in AD model mice.

    View all comments by Gregory Cole
  2. This paper from He et al. adds to the mounting evidence that omega-3 polyunsaturated fatty acids exert a neuroprotective action in the brain. In the various experimental paradigms presented, Fat-1 mice were protected from the deleterious effects of a diet almost completely deprived of omega-3 fatty acids (omega-6:omega-3 ratio over 1,000). Overall, the dendritic spine counts as well as neurogenesis and cognition data confirm the results of previous dietary studies using omega-3 depletion/supplementation. It would have been interesting to see whether the observed effects also apply to aging animals when the need for adequate omega-3 supply might be even more acute.

    View all comments by Frederic Calon

References

News Citations

  1. Fish Oil Swims Ahead in Dietary Brain Protection Race
  2. First Trial of Fish Fats Shows Promise for Early AD
  3. Talking Fish Fat And Cholesterol

Paper Citations

  1. . Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45. PubMed.
  2. . Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed.
  3. . Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003 Jul;60(7):940-6. PubMed.
  4. . Gene and protein expression profiling of the fat-1 mouse brain. Prostaglandins Leukot Essent Fatty Acids. 2009 Jan;80(1):33-42. PubMed.
  5. . Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):213-21. PubMed.

Further Reading

Papers

  1. . Omega-3 fatty acids and dementia. Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):213-21. PubMed.
  2. . Gene and protein expression profiling of the fat-1 mouse brain. Prostaglandins Leukot Essent Fatty Acids. 2009 Jan;80(1):33-42. PubMed.

Primary Papers

  1. . Improved spatial learning performance of fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. Proc Natl Acad Sci U S A. 2009 Jun 22; PubMed.