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A. H. Neufeld, H. Chen, B. Liu, T. J. Lukas; The Aged Retinal Pigment Epithelium/Choroid: An Underlying Substratum for the Pathogenesis of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):223. doi: https://doi.org/.
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To characterize changes in the retinal pigment epithelium (RPE)/choroid with age that may provide a background for the development of age-related macular degeneration (AMD).
mRNA was isolated from the RPE/choroid and neural retina of young (4 mos) and old (26 mos) mice and comparisons using Affymetrix microarrays were performed. Data were analyzed using 3 independent statistical methods (Limma, Dchip and SAM) to identify the differentially expressed genes in RPE/choroid from old animals. Differentially expressed genes were analyzed for global functions, networks and canonical pathways using Ingenuity Pathway Analysis. The results were confirmed by quantitative real time (qrt) RT-PCR.
There were marked differences in the old mouse in the gene expression patterns of the RPE/choroid. Most of the 227 genes in common using the three analytical methods were upregulated in the RPE/choroid from old animals and were related to immune responses and inflammatory activity. The fold changes of selected genes from each canonical pathway were confirmed by qrt RT-PCR. Using Ingenuity Pathway Analysis, the 5 canonical pathways that showed the most significant upregulation in aged RPE/choroid were leukocyte extravasation signaling, complement cascades, natural killer cell signaling, IL-10 signaling, and B cell receptor signaling. By contrast, the adjacent neural retina showed completely different age-related changes in its transcriptional profile. Consistent with the microarray data, using leukocyte marker CD45, we found marked extravasation from the choroidal circulation and accumulation of leukocytes on RPE/Bruch’s membrane in old animals, but not in young animals.
These marked age-related changes in the normal RPE/choroid suggest that the tissue has become immunologically active in old animals. Normal, age-related phenotypic changes in the RPE/choroid provide the altered background for a mutation in a gene that participates in the regulation of leukocyte functions to cause dysregulation in an elderly individual. These phenotypic changes may underlie the pathogenesis of AMD.
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