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Anthony John Day, Alex Langford-Smith, Viranga Tilakaratna, Larisa Logunova, Paul Lythgoe, Simon John Clark, Paul N Bishop; Age-related accumulation of metal ions in Bruch’s membrane: implications for AMD. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6559.
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© ARVO (1962-2015); The Authors (2016-present)
A major hallmark of age-related macular degeneration (AMD) is the accumulation of extracellular debris (including drusen) around the interface between Bruch’s membrane (BM) and the retinal pigment epithelium (RPE). Multiple genetic and environmental risk factors have been identified, whereas, the role of normal ageing is less well characterized. Here we have investigated the age-related accumulation of metal ions in the BM and how this affects the function of the adjacent RPE.
We analysed eyes from human donors without known AMD (aged 11-88 years) and quantified the level of 14 metal ions in BM preparations by inductively coupled plasma mass spectrometry (ICPMS) (n=131), determined gene expression changes in the adjacent RPE cells by quantitative PCR (n=81) and transcriptomics (n=24), and performed histological analysis on the macula regions from the contralateral eyes (n=45).
ICPMS revealed a significant linear increase in cadmium and cobalt ions, and a decrease in zinc ions, with age. Furthermore we identified a population of older donors with high levels of aluminium; histological Walton staining localised this metal ion to the BM and RPE (it was also present in drusen in 5 AMD donors). The amounts of metal ions in the BM (e.g. Al3+, Cd2+, Co2+, Zn2+) correlated with RPE gene expression changes in components of the oxidative stress and complement pathways and of the major AMD risk factor, HTRA1; multivariate analysis revealed that aluminium was one of the most important factors influencing gene expression, more so than age alone. However, age and Cd2+ and Co2+ correlated with histological changes in carboxymethyl lysine (an oxidative stress marker) and the terminal complement complex in the BM of the contralateral eye. Analysis of the transcriptomics data further demonstrated that pathways associated with oxidative stress and complement correlated with certain metal ions in the adjacent BM, and additionally identified changes in eumelanin biosynthesis, mitochondrial dysfunction, autophagy and proteasomal activity with age; in the case of Al3+, this was also highly associated with vasculogenesis.
Overall this study has identified that several metal ions accumulate in human BM during normal ageing, and are associated with gene expression changes in multiple pathways implicated in AMD initiation and progression.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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