Initiating Events in AMD: An Animal Model for the Human Disease

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The broad, long-term objective of this proposal is to define in molecular terms the linkage between the oxidative modifications of proteins in the outer retina, their recognition by the immune system and the vulnerability of the outer retina to attack, leading to the disease processes underlying age-related macular degeneration (AMD). Work completed during the last grant period revealed that AMD eye tissues contain high levels of proteins modified by the adduction of oxidation fragments of the long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA). Many of the proteins modified by this and other adducts are found in drusen and Bruch's membrane. Furthermore, autoantibodies against these unique carboxyethylpyrrole adducts (CEP) are more abundant in the circulation (plasma) of individuals with AMD than are found in agematched individuals without AMD. From these results the following hypothesis has emerged regarding an initiating stimulus for AMD: (a). Because of the high concentration of DHA in the photoreceptors-RPE complex coupled with the vulnerability of DHA to oxidative damage, CEP-adducts are slowly generated over time in the outer retina, (b). These CEP-adducts represent new epitopes foreign to the immune system resulting in the generation of autoantibodies against CEP. (c). Anti-CEP-antibodies in turn are involved in activation of the complement attack pathway at the Bruch's membrane-RPE interface in response to the continued generation of CEP epitopes in tissues of the outer retina. To test this hypothesis we immunized normal mice with CEP-adducted mouse serum albumin. Our prediction was that systemic immunization with CEP would sensitize mice to endogenous CEP-adducted proteins generated in the outer retina during the normal course of aging. In turn the immune system would respond by attacking the cells where CEP epitopes are most readily generated. Analysis of these mice demonstrated focal lesions in the RPE and photoreceptors that mimic geographic atrophy, the blinding end-stage atrophy associated with dry AMD. This new mouse model for AMD will be further characterized in normal mice and the CEP-immunizations will be extended to mice with genetic defects in complement pathway molecules and their regulators. A new model for AMD in the mouse will be an important a new resource for use in the preclinical testing of therapeutics designed to prevent or limit the progression of AMD.