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Oxidative Modifications as Triggers of AMD Pathology

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Studies on Retinal and Choroidal Disorders

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Abstract

Age-related macular degeneration (AMD), a leading cause of blindness in the elderly, is thought to be in part an inflammatory disease involving dysregulation of the complement system. The photooxidative environment in the retina facilitates the formation of oxidative modifications that contribute to the accumulation of cellular debris such as lipofuscin within the retinal pigment epithelium (RPE) and drusen on Bruch’s membrane. A host of oxidative modifications have been found in AMD tissues, including carboxymethyllysine (CML), pentosidine, carboxyethylpyrrole (CEP), nitrotyrosine, 8-hydroxydeoxyguanosine, levuglandin/isolevuglandin-phosphatidyl ethanolamine hydroxylactams, and other adducts involving iso[4]levuglandin E2, hydroxynonenal, and acrolein. Oxidative modifications also generate oxidation-associated molecular patterns recognized by pattern-recognition receptors such as the complement system, the receptor for advanced glycation end products (RAGE), and the toll-like receptors. CML is a strong activator of RAGE, colocalizes with RAGE in AMD ocular tissues, is elevated in AMD plasma, and stimulates expression of vascular endothelial growth factor (VEGF) and angiogenesis. CEP adducts activate toll-like receptor 2, are elevated in AMD Bruch’s membrane/RPE/choroid and AMD plasma, and stimulate neovascularization independent of VEGF. Mice immunized with CEP develop an AMD-like phenotype. Photoxidation of RPE lipofuscin can result in activation of complement and generation of advanced glycation end products. Mounting evidence implicates oxidative modifications as triggers and catalysts of inflammatory and immune responses in AMD pathology.

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  1. Departments of Ophthalmology and Molecular Medicine, Cole Eye Institute and Lerner Research Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    John W. Crabb

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    Robert D. Stratton

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    William W. Hauswirth

  3. Molecular and Integrative Physiology, Ophthalmology and Visual Sciences, Kellogg Eye Center, Wall Street 1000, Ann Arbor, 17033-2390, Michigan, USA

    Thomas W. Gardner

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Crabb, J.W. (2012). Oxidative Modifications as Triggers of AMD Pathology. In: Stratton, R., Hauswirth, W., Gardner, T. (eds) Studies on Retinal and Choroidal Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press. https://doi.org/10.1007/978-1-61779-606-7_3

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