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T. Langmann, S. Ebert, K. Weigelt, Y. Walczak, W. Drobnik, R. Mauerer, D. A. H. Hume, B. H. F. Weber; Docosahexaenoic Acid Protects From Early Retinal Degeneration and Attenuates Microglial Activation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6253.
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© ARVO (1962-2015); The Authors (2016-present)
Microgliosis is a common phenomenon in retinal dystrophies. Our first goal was to perform a molecular and functional characterization of activated microglia in the retinoschisin-deficient (Rs1h-/Y) mouse model of inherited retinal degeneration. Moreover, we aimed to study the effects of of dietary docosahexaenoic acid (DHA) on retinal degeneration and microglia activity in Rs1h-/Y mice.
To visualize and isolate activated microglia, Rs1h-/Y animals were crossed with transgenic MacGreen mice, which express the enhanced green fluorescent protein (EGFP) under the control of the macrophage-specific csf1r promoter. Microarray analysis and high-throughput real-time RT-PCR were performed for molecular profiling of cultured activated and resting microglia. A DHA supplementation study was carried out with Rs1h-/Y mice and lipid profiles of the retina, brain and plasma were determined by gas-chromatography mass-spectrometry. Retinal histology, photoreceptor apoptosis, inflammatory markers and microglia phenotypes were analyzed.
Lipid droplet-containing activated microglia were detected in retinal sections of early postnatal Rs1h-/Y / MacGreen mice before the onset of overt neuronal cell death. Microarray analysis of ex vivo isolated microglia revealed induction of a gene set involved in lipid droplet formation and eicosanoid synthesis. Analysis of the retinal phospholipid composition of Rs1h-/Y and wild-type retinas revealed a significant decrease in the omega-3-polyunsaturated fatty acid DHA. To establish a potential link between microglia activation, reduced DHA levels, and neurodegeneration in the retina, a dietary intervention study was performed. Female Rs1h-/- mice and their Rs1h-/Y litter were either subjected to a diet enriched with 2% DHA, or a standard chow. Supplementation with DHA enhanced photoreceptor survival and converted lipid-bloated microglia to a quiescent phenotype with reduced pro-inflammatory gene expression. As a consequence, retinal DHA levels may control the activity of microglia and thereby may affect the progression and extent of retinal degeneration.
We conclude that dietary DHA supplementation could be a treatment option for inherited retinal degeneration that restores both microglial homeostasis and neuronal viability.
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