The complex relationship between omega-3 fatty acids and neurodegenerative diseases

Redoxoma Highlights by Sayuri Miyamoto

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is well known by its health-promoting effects. Being highly abundant in the brain, DHA displays essential role in neurological and visual development in infants. In adults, the decline of DHA content in brain has been associated to cognitive impairment and the use of omega-3 supplements have been thought to exert neuroprotective effects. Indeed, some studies indicated that consuming DHA would be beneficial for the prevention of cognitive disorders such as Alzheimer's disease [1]. However, a recent clinical study involving 4000 participants has found no statistically significant difference between the groups that received omega-3 supplements vs the placebo group [2]. Discrepant results on omega-3 benefits has been also reported for another neurodegenerative disease, amyotrophic lateral sclerosis (ALS). While an observational study reported that a diet rich in omega-3 may lower the risk for ALS [3], a contrasting result was observed in another study, in which omega-3 supplementation in the form of eicosapentaenoic acid (EPA) accelerated disease progression in a mouse model of ALS [4]. Animals that were pretreated with EPA showed increased cellular damage and vacuolization within the spinal cord. These effects have been attributed to the presence of increased amounts of lipid-derived oxidation products and superoxide dismutase1 (SOD1) aggregates. To corroborate with the latter hypothesis, a recent study by Appolinario et al. [5], from the group of Sayuri Miyamoto, a principal investigator of CEPID-Redoxoma, demonstrated that DHA induces the aggregation of both wild type and G93A mutant form of apo(without metals)-Cu,Zn-SOD1 in vitro [5]. Interestingly, the study by Appolinario et al. revealed that the oxidized counterpart of DHA (DHA hydroperoxides) induces a distinct pattern of SOD1 aggregation in which aberrant SOD1 dimeric species are produced. Since such SOD1 dimeric aggregates have been thought to be involved in neurodegerative processes, results of this study raise an important question and indicate that further research is needed to understand the role DHA and its oxidized derivatives in ALS disease development. In summary, although epidemiological studies suggest that omega-3 supplements may be beneficial, care should be taken when adopting any supplementation before its efficacy is proven by scientific studies and clinical trials.

1. M. Fotuhi, P. Mohassel, K. Yaffe. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association Nature Reviews Neurology, 5, 140-52, 2009 | doi: 10.1038/ncpneuro1044
2. E. Y. Chew, T. E. Clemons, E. Agrón, L. J. Launer. Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function The Journal of American Medical Association, 314(8): 791-801, 2015 | doi: 10.1001/jama.2015.9677
3. K. C. Fitzgerald, É. J. O’Reilly, G. J. Falcone, M. L. McCullough, Y. Park, L. N. Kolonel, A. Ascherio. Dietary ω-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis JAMA Neurology, 71(9): 1102-10, 2014 | doi: 10.1001/jamaneurol.2014.1214
4. P. K. Yip, C. Pizzasegola, S. Gladman, M. L. Biggio, M. Marino, M. Jayasinghe, F. Ullah, S. C. Dyall, A. Malaspina, C. Bendotti, A. Michael-Titus. The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis PLoS One, 8(4): e61626, 2013 | doi: 10.1371/journal.pone.0061626
5. P. P. Appolinário, D. B. Medinas, A. B. Chaves-Filho, T. Genaro-Mattos, J. R. R. Cussiol, L. E. S. Netto, O. Augusto, S. Miyamoto. Oligomerization of Cu, Zn-superoxide dismutase (SOD1) by docosahexaenoic acid and its hydroperoxides in vitro: aggregation dependence on fatty acid unsaturation and thiols PLoS One, 10(4): e0125146, 2015 | doi: 10.1371/journal.pone.0125146

Sayuri Miyamoto, PhD Associate Professor, Departament of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.