Advanced glycation end product (AGE) accumulation on Bruch's membrane: Links to age-related RPE dysfunction

Josephine V. Glenn, Helen Mahaffy, Keqiang Wu, Gill Smith, Ryoji Nagai, David A.C. Simpson, Michael E. Boulton, Alan W. Stitt

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

PURPOSE. Advanced glycation end products (AGEs) accumulate during aging and have been observed in postmortem eyes within the retinal pigment epithelium (RPE), Bruch's membrane, and subcellular deposits (drusen). AGEs have been associated with age-related dysfunction of the RPE-in particular with development and progression to age-related macular degeneration (AMD). In the present study the impact of AGEs at the RPE-Bruch's membrane interface was evaluated, to establish how these modifications may contribute to age-related disease. METHODS. AGEs on Bruch's membrane were evaluated using immunohistochemistry. A clinically relevant in vitro model of substrate AGE accumulation was established to mimic Bruch's membrane ageing. Responses of ARPE-19 growing on AGE-modified basement membrane (AGE-BM) for 1 month were investigated by using a microarray approach and validated by quantitative (q)RT-PCR. In addition to identified AGE-related mRNA alterations, lysosomal enzyme activity and lipofuscin accumulation were also studied in ARPE-19 grown on AGE-BM. RESULTS. Autofluorescent and glycolaldehyde-derived AGEs were observed in clinical specimens on Bruch's membrane and choroidal extracellular matrix. In vitro analysis identified a range of dysregulated mRNAs in ARPE-19 exposed to AGE-BM. Altered ARPE-19 degradative enzyme mRNA expression was observed on exposure to AGE-BM. AGE-BM caused a significant reduction in cathepsin-D activity in ARPE-19 (P < 0.05) and an increase in lipofuscin accumulation (P < 0.01). CONCLUSIONS. AGEs influence ARPE-19 mRNA expression pro-files and may contribute to reduced lysosomal enzyme degradative capacity and enhanced accumulation of lipofuscin. Formation of AGEs on Bruch's membrane may have important consequences for age-related dysfunction of the RPE, perhaps leading to age-related outer retinal disease.

Original languageEnglish (US)
Pages (from-to)441-451
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number1
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Glenn, J. V., Mahaffy, H., Wu, K., Smith, G., Nagai, R., Simpson, D. A. C., Boulton, M. E., & Stitt, A. W. (2009). Advanced glycation end product (AGE) accumulation on Bruch's membrane: Links to age-related RPE dysfunction. Investigative Ophthalmology and Visual Science, 50(1), 441-451. https://doi.org/10.1167/iovs.08-1724