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J. Ambati, A. Anand, E. Sakurai, W.A. Kuziel, B.J. Rollins, B.K. Ambati; An Animal Model of Age-related Macular Degeneration in Senescent Macrophage Recruitment Impaired Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1718.
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Purpose: To characterize the development of age-related macular degeneration (AMD)-like pathology in senescent mice genetically deficient either in monocyte chemoattractant protein-1 (MCP-1) or its C-C chemokine receptor-2 (CCR2), and to dissect the molecular etiology of this phenotype. Methods: Wildtype, MCP-1 -/-, and CCR2 -/- deficient mice were examined from 0-24 months of age by fundus photography, indocyanine green angiography, immunohistochemistry, and transmission electron microscopy. Human retinal pigment epithelium (RPE) cells were exposed to protein deposits identified in knockout mice. Results: MCP-1 -/- and CCR2 -/- mice develop lipofuscin, thickening of Bruch’s membrane, drusenoid deposits, focal and diffuse RPE atrophy, and choroidal neovascularization in an age-related fashion. Deposition of complement component C5, immunoglobulin G (IgG), and advanced glycation endproducts (AGE) in the RPE accompanies senescence in these knockout mice as in patients with AMD. C5, IgG, and AGE induce human RPE cell production of MCP-1 and vascular endothelial growth factor (VEGF). Wildtype mice demonstrate increased expression of MCP-1 in the RPE as they age. Conclusions: Immune/inflammatory deposits that accumulate in senescent knockout mice stimulate RPE cells to produce MCP-1, suggesting that MCP-1/CCR2 deficiency prevents the normal clearance of these protein deposits, which in turn may contribute to the development of an AMD-like phenotype.
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