the aged retinal pigment epitheliumchoroid a potential substratum for the pathogenesis of age-related macular degeneration老年人视网膜色素epitheliumchoroid潜在的年龄相关性黄斑变性的发病机制的基础.pdf

The Aged Retinal Pigment Epithelium/Choroid: A Potential Substratum for the Pathogenesis of Age- Related Macular Degeneration Huiyi Chen, Bin Liu, Thomas J. Lukas, Arthur H. Neufeld* Forsythe Laboratory for the Investigation of the Aging Retina, Department of Ophthalmology, Northwestern University School of Medicine, Chicago, Illinois, United States of America Abstract Background: Although the statement that age is the greatest risk factor for Age-related macular degeneration (AMD) is widely accepted, the cellular and molecular explanations for that clinical statement are not generally known. A major focus of AMD research is the retinal pigment epithelium (RPE)/choroid. The purpose of this study was to characterize the changes in the RPE/choroid with age that may provide a background for the development of AMD. Methodology/Principal Findings: We compared the transcriptional profiles, key protein levels and histology of the RPE/ choroid from young and old mice. Using three statistical methods, microarray data demonstrated marked changes in the old mouse. There were 315 genes differentially expressed with age; most of these genes were related to immune responses and inflammatory activity. Canonical pathways having significant numbers of upregulated genes in aged RPE/choroid included leukocyte extravasation, complement cascades, natural killer cell signaling and IL-10 signaling. By contrast, the adjacent neural retina showed completely different age-related changes. The levels of proteins that participate in leukocyte extravasation and complement pathways were consistently increased in the normal, aged RPE/choroid. Furthermore, there was increased gene expression and protein levels of leukocyte attracting signal, chemokine ligand 2 (Ccl2) in aged RPE/ choroid. In old animals, there was marked extravasation and accumulation of leukocytes from the choroi