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      Age and disease-related structural changes in the retinal pigment epithelium

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          Abstract

          As the retinal pigment epithelium (RPE) ages, a number of structural changes occur, including loss of melanin granules, increase in the density of residual bodies, accumulation of lipofuscin, accumulation of basal deposits on or within Bruch’s membrane, formation of drusen (between the basal lamina of the RPE and the inner collagenous layer of Bruch’s membrane), thickening of Bruch’s membrane, microvilli atrophy and disorganization of the basal infoldings. Although these changes are well known, the basic mechanisms involved in them are frequently poorly understood. These age-related changes progress slowly and vary in severity in different individuals. These changes are also found in age-related macular degeneration (AMD), a late onset disease that severely impacts the RPE, but they are much more pronounced than during normal aging. However, the changes in AMD lead to severe loss of vision. Given the many supporting functions which the RPE serves for the retina, it is important to decipher the age-related changes in this epithelium in order to understand age-related changes in vision.

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          Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

          John W. Crabb, Masaru Miyagi, Xiaorong GU … (2002)
          Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.
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            A role for local inflammation in the formation of drusen in the aging eye.

            Don H Anderson, Robert F. Mullins, Gregory Hageman … (2002)
            The accumulation of numerous or confluent drusen, especially in the macula, is a significant risk factor for the development of age-related macular degeneration (AMD). Identifying the origin and molecular composition of these deposits, therefore, has been an important, yet elusive, objective for many decades. Recently, a more complete profile of the molecular composition of drusen has emerged. In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. Tissue specimens from one or both eyes of more than 400 human donors were examined by light, confocal or electron microscopy, in conjunction with antibodies to specific drusen-associated proteins, to help characterize the transitional events in drusen biogenesis. Quantification of messenger RNA from the retinal pigment epithelium (RPE)/choroid of donor eyes was used to determine if local ocular sources for drusen-associated molecules exist. The results indicate that cellular remnants and debris derived from degenerate RPE cells become sequestered between the RPE basal lamina and Bruch's membrane. We propose that this cellular debris constitutes a chronic inflammatory stimulus, and a potential "nucleation" site for drusen formation. The entrapped cellular debris then becomes the target of encapsulation by a variety of inflammatory mediators, some of which are contributed by the RPE and, perhaps, other local cell types; and some of which are extravasated from the choroidal circulation. The results support a role for local inflammation in drusen biogenesis, and suggest that it is analogous to the process that occurs in other age-related diseases, such as Alzheimer's disease and atherosclerosis, where accumulation of extracellular plaques and deposits elicits a local chronic inflammatory response that exacerbates the effects of primary pathogenic stimuli.
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              The role of oxidative stress in the pathogenesis of age-related macular degeneration.

              S Beatty, H. Koh, M Phil … (2000)
              Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Clin Ophthalmol
                Journal ID (publisher-id): Clinical Ophthalmology
                Title: Clinical ophthalmology (Auckland, N.Z.)
                Publisher: Dove Medical Press
                ISSN (Print): 1177-5467
                ISSN (Electronic): 1177-5483
                Publication date (Print): June 2008
                Volume: 2
                Issue: 2
                Pages: 413-424
                Affiliations
                Cole Eye Institute, The Cleveland Clinic, Cleveland, OH, USA
                Author notes
                Correspondence: Vera L Bonilha, Cole Eye Institute (i31), The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA, Tel +1 216 445 7690, Fax +1 216 445 3670, Email bonilhav@ 123456ccf.org
                Article
                Publisher ID: co-2-413
                DOI: 10.2147/OPTH.S2151
                PMC ID: 2693982
                PubMed ID: 19668732
                SO-VID: 6b154c02-0688-447f-b4a6-f8a6446c0ac6
                Copyright © © 2008 Bonilha, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
                History
                Categories
                Subject: Review

                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: ocular disorders,aging,age-related macular degeneration (amd),retinal pigment epithelium,retinal disease
                Data availability:
                ScienceOpen disciplines: Ophthalmology & Optometry
                Keywords: ocular disorders, aging, age-related macular degeneration (amd), retinal pigment epithelium, retinal disease

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