A role for local inflammation in the formation of drusen in the aging eye

A role for local inflammation in the formation of drusen in the aging eye PURPOSE: 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. DESIGN: In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Ophthalmology Elsevier

A role for local inflammation in the formation of drusen in the aging eye

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Abstract

PURPOSE: 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. DESIGN: In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Journal

American Journal of OphthalmologyElsevier

Published: Sep 1, 2002

References

  • Molecular genetics of age-related macular degeneration
    Stone, E.M.; Sheffield, V.C.; Hageman, G.S.
  • Drusen in age-related macular degeneration
    Abdelsalam, A.; Del Priore, L.; Zarbin, M.A.
  • Age-related maculopathy
    Sarks, S.H.; Sarks, J.P.
  • Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium
    Anderson, D.H.; Ozaki, S.; Nealon, M.
  • Location, substructure, and composition of basal laminar drusen compared with drusen associated with aging and age-related macular degeneration
    Russell, S.R.; Mullins, R.F.; Schneider, B.L.; Hageman, G.S.
  • Apolipoprotein E and atherosclerosis
    Davignon, J.; Cohn, J.S.; Mabile, L.; Bernier, L.
  • The human retina and retinal pigment epithelium are abundant sources of vitronectin mRNA
    Ozaki, S.; Johnson, L.V.; Mullins, R.F.; Hageman, G.S.; Anderson, D.H.
  • Extrahepatic complement biosynthesis
    Morgan, B.P.; Gasque, P.
  • Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain
    Shen, Y.; Li, R.; McGeer, E.G.; McGeer, P.L.

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