Age-related macular degeneration (AMD) is a degenerative condition that begins in Bruch's membrane and progresses to involve the retinal pigment epithelium and ultimately the overlying photoreceptors. The only required etiologic factor is age, and AMD is regarded as the leading cause of blindness in individuals older than 65 years. AMD results from variable contributions of age, environment, and genetic predisposition. Many loci are linked to AMD; in the majority of cases, the disease is associated with polymorphisms within these genes, rather than mutations that ablate gene function. The etiologic complexity of AMD is reflected by the paucity of animal models that entirely replicate the human disease. This review compares the salient anatomy of the primate and rodent retina, particularly in the light of AMD pathology. It next discusses prevailing hypotheses explaining how AMD may develop. These include the role of complement activation and macrophage chemotaxis in AMD, molecular mechanisms of choroidal neovascularization, and the roles of oxidative damage and lipid metabolism. Finally, the article gives an overview of spontaneous and induced nonhuman primate models and describes relevant mouse models in the context of each pathogenetic mechanism.
KeywordsBruch's membrane, choriocapillaris, complement, degeneration, macula, retinal pigment epithelium Age-related macular degeneration (AMD) is a progressive condition of the retinal pigment epithelium (RPE), its supporting basement membrane, and the overlying photoreceptor layer. It affects the macula, the central area of the retina responsible for high-acuity daylight vision. Among individuals older than 65 years, AMD is regarded as the leading cause of blindness in the industrialized world.
39AMD has no single cause and results from variable contributions of age, genetic predisposition, and environment. Established epidemiologic risk factors include cigarette smoking, diet, female sex, Caucasian race, and a family history of AMD.52,60,61 Because AMD is rare in individuals younger than 55 years, the only required risk factor is age, which implicates the multitude of cellular changes that accompany normal aging in the pathogenesis of AMD. The challenge is to identify how these are altered to tip the process toward overt disease.With age, most people accumulate small, well-demarcated deposits of extracellular material beneath the RPE. 5,45 These are known as small, hard drusen and are not pathogenic. However, if these deposits enlarge, they become associated with regional RPE loss and eventual degeneration of overlying photoreceptors. These changes are funduscopically visible, and their progression is used to classify lesions along the continuum of early to late dry AMD. 18 The pathogenetic mechanisms of this process center on inflammation, oxidative damage, and RPE senescence 45 and are predominantly modeled in the mouse.In the minority of cases, late AMD is accompanied by growth of blood vessels from the choroid through Bruch's membrane toward the retina. ...