29 June 2009. 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.
He C, Qu X, Cui L, Wang J, Kang JX. Improved spatial learning performance of Fat-1 mice is associated with enhanced neurogenesis and neuritogenesis by docosahexaenoic acid. 2009 June. Abstract