Current Concepts in the Pathogenesis of Age-Related Macular Degeneration

Abstract

To review and synthesize information concerning the pathogenesis of age-related macular degeneration (AMD).Methods: Review of the English-language literature.Results: Five concepts relevant to the cell biology of AMD are as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes retinal pigment epithelial (RPE) and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix (ECM), which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and(5) the abnormal ECM results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, both the environment and multiple genes can alter a patient's susceptibility to AMD. Implicit in this characterization of AMD pathogenesis is the concept that there is linear progression from one stage of the disease to the next. This assumption may be incorrect, and different biochemical pathways leading to geographic atrophy and/or choroidal new vessels may operate simultaneously.Conclusions: Better knowledge of AMD cell biology will lead to better treatments for AMD at all stages of the disease. Many unanswered questions regarding AMD pathogenesis remain. Multiple animal models and in vitro models of specific aspects of AMD are needed to make rapid progress in developing effective therapies for different stages of the disease.

Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe

“…Chronic retinal inflammation in humans is expected to cause iron overload within the retina, but whether such effects have any relevance to the pathogenesis of age-related macular degeneration remains to be seen. It is interesting to note that genetic variations in genes involved in inflammation and oxidative stress, including the Toll-like receptor-4 [43], have been implicated in the pathogenesis of age-related macular degeneration [44][45][46].…”

Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial

“…There is interest in the use of nutrition as a prevention and treatment strategy for age-related macular disease (ARMD) as it is the leading cause of visual disability in the developed World (Klein et al, 1997), and because treatment options are currently lacking (Zarbin, 2004). According to an international classification and grading system (Bird et al, 1995), this condition can be divided into early (age-related maculopathy, (ARM)) and late (age-related macular degeneration, (AMD)) stages.…”

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

“…The mechanism of this disease remains elusive and current therapeutic options are limited. An increasing body of literature indicates that development of AMD is related to dysfunction of RPE (Boulton et al, 2004;Zarbin, 2004;Zhou et al, 2005). One essential function of the postmitotic RPE is phagocytosis and degradation of shed photoreceptor outer segments.…”