Oxidative damage and inflammation are postulated to be involved in age-related macular degeneration (AMD). However, the molecular signal(s) linking oxidation to inflammation in this late-onset disease is unknown. Here we describe AMD-like lesions in mice after immunization with mouse serum albumin adducted with carboxyethylpyrrole, a unique oxidation fragment of docosahexaenoic acid that has previously been found adducting proteins in drusen from AMD donor eye tissues1 and in plasma samples2 from individuals with AMD. Immunized mice develop antibodies to this hapten, fix complement component-3 in Bruch's membrane, accumulate drusen below the retinal pigment epithelium during aging, and develop lesions in the retinal pigment epithelium mimicking geographic atrophy, the blinding end-stage condition characteristic of the dry form of AMD. We hypothesize that these mice are sensitized to the generation of carboxyethylpyrrole adducts in the outer retina, where docosahexaenoic acid is abundant and conditions for oxidative damage are permissive. This new model provides a platform for dissecting the molecular pathology of oxidative damage in the outer retina and the immune response contributing to AMD.
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J.G.H. and V.L.P. designed and initiated the experiments. L.L. and R.G.S. prepared the CEP-MSA and CEP-BSA. R.L.U., V.L.P., K.G.S. and X.Y. immunized the mice. K.G.S. and X.Y. performed the protein chemistry and ELISA assays, as well as managing the day-to-day maintenance of the mice. M.E.R. and J.G.H. performed all of the histological and electron microscopic analysis. V.L.B. performed the confocal microscopy. J.G.H. analyzed all of the data and wrote the manuscript. R.G.S., R.L.U. and V.L.P. made critical comments and suggestions for revisions of the manuscript in response to the reviewers.
The mouse model for age-related macular degeneration described in this study is protected for commercialization by the Cleveland Clinic. J.G.H., R.G.S. and V.L.P. are the inventors.
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Hollyfield, J., Bonilha, V., Rayborn, M. et al. Oxidative damage–induced inflammation initiates age-related macular degeneration. Nat Med 14, 194–198 (2008). https://doi.org/10.1038/nm1709
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