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.
Proc Natl Acad Sci U S A. 2009 Jun 22;
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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.
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.
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