Neuroinflammation is a recognized hallmark of Alzheimer's disease, along with accumulation of amyloid-β plaques, neurofibrillary tangles and synaptic loss. n-3 polyunsaturated fatty acids (PUFA) and molecules derived from them, including eicosapentaenoic acid-derived eicosanoids and docosahexaenoic acid-derived docosanoids, are known to have both anti-inflammatory and pro-resolving properties, while human observational data links consumption of these fatty acids to a decreased risk of Alzheimer's disease. Few studies have examined the neuroinflammation-modulating effects of n-3 PUFA feeding in an Alzheimer's disease-related model, and none have investigated whether these effects are mediated by changes in brain eicosanoids and docosanoids. Here, we use both a fat-1 transgenic mouse and a fish oil feeding model to study the impact of increasing tissue n-3 PUFA on neuroinflammation and the production of pro-inflammatory and pro-resolving lipid mediators.
Fat-1 mice, transgenic animals that can convert n-6 to n-3 PUFA, and their wildtype littermates were fed diets containing either fish oil (high n-3 PUFA) or safflower oil (negligible n-3 PUFA) from weaning to 12 weeks. Animals then underwent intracerebroventricular infusion of either amyloid-β 1-40 or a control peptide. Hippocampi were collected from non-surgery and surgery animals 10 days after infusion. Microarray was used to measure enrichment of inflammation-associated gene categories and expression of genes involved in the synthesis of lipid mediators. Results were validated by real-time PCR in a separate cohort of animals. Lipid mediators were measured via liquid chromatography tandem mass spectrometry.
Fat-1 and wildtype mice fed fish oil had higher total hippocampal DHA than wildtype mice fed the safflower oil diet. The safflower-fed mice, but not the fat-1 or fish oil-fed mice, had significantly increased expression in gene ontology categories associated with inflammation in response to amyloid-β infusion. These effects were independent of changes in the expression of genes involved in the synthesis of eicosanoids or docosanoids in any group. Gene expression was replicated upon validation in the wildtype safflower and fish oil-fed, but not the fat-1 mice. Protectin, maresin and D and E series resolvins were not detected in any sample. There were no major differences in levels of other eicosanoids or docosanoids between any of the groups in response to amyloid-β infusion.
Fish oil feeding decreases neuroinflammatory gene expression in response to amyloid-β. Neither amyloid-β infusion or increasing brain DHA affects the brain concentrations of specialized pro-resolving mediators in this model, or the concentrations of most other eicosanoids and docosanoids.