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Wenxin Ma, Radu Cojocaru, Norimoto Gotoh, Linn Gieser, Rafael Villasmil, Tiziana Cogliati, Anand Swaroop, Wai Wong, ; Gene Expression Changes in Aging Retinal Microglia: Relationship to Microglial Support Functions and Regulation of Microglial Activation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5582.
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Microglia feature in the pathogenesis of many age-related neurodegenerative disorders, including age-related macular degeneration. It has been hypothesized that microglia may undergo aging changes that give rise to pathogenically relevant microglial phenotypes that help drive disease progression. To understand microglial aging in the retina, we compared the gene expression profiles in microglia isolated ex vivo from the retinas of wild type mice at different ages ranging from early adulthood to late senescence.
CD11b+ microglia were isolated using flow cytometry from the retinas of 3 month, 12 month, 18 month and 24 month old C57BL/6 mice in which the Crb1 rd8 mutation was confirmed as being absent. mRNA was extracted, amplified and reverse-transcribed to cDNA, and labeled with biotin. The labeled target (5 µg) was applied to a GeneChip Mouse Exon 1.0ST Array, hybridized on an Affymetrix GeneChip Fluidics Station 450, and then scanned with a GeneChip Scanner 3000 7G. Age-specific gene expression profiles were analyzed and compared using the GeneSpring GX 11.0.2 software. Age-related differences in expression levels of specific genes were confirmed using qPCR and immunohistochemistry.
Microglial gene expression profiles demonstrated progressive change with increasing age. We identified a total of 719 genes (out of a total of 16711) that showed differential expression of >1.5-fold change at p<0.05 (uncorrected one-way ANOVA) for at least one of the 3 age-group comparisons. Age-regulated genes were present in molecular pathways involving microglial immune function and regulation, angiogenesis, and neurotrophin signaling demonstrated age-related change. In particular, expression levels of complement genes, C3 and CFB, previously associated with age-related macular degeneration (AMD), were increased with aging, suggesting that senescent microglia may contribute to complement dysregulation during disease pathogenesis.
Aging retinal microglia demonstrates age-related gene expression changes that are capable of altering their constitutive support functions and regulation of their activation status in ways that may potentially relate to neurodegeneration and neuroinflammation in the CNS.
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