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Zsolt Ablonczy, Daniel Higbee, Anne M. Hanneken, Kevin L. Schey, Yiannis Koutalos, Rosalie K. Crouch; Linking Retinoids To Clinical Patterns Of Amd. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6477. doi: https://doi.org/.
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Byproducts of the retinoid visual cycle can accumulate in the retinal pigment epithelium (RPE) and contribute to both the fluorescence of lipofuscin and its toxicity during the development of age-related macular degeneration. Clinical imaging has established a relationship between RPE fluorescence and hotoreceptor damage. However, the apparent distribution of A2E, a major retinoid-derived component of lipofuscin, disagrees with the clinical pattern of AMD. Therefore, the molecular link between retinoids and disease is yet to be identified.
To understand the spatial distribution and relationships of lipofuscin and retinoid-derived metabolites, fluorescence and matrix-assisted laser desorption/ionization (MALDI) imaging was used in human tissue samples from the entire lifespan. Selected samples were correlated with micrographs of the fundus and prior clinical observations. To study the accumulation of retinoid-derived metabolites and their contribution to lipofuscin, we utilized an in vitro model system (fetal human RPE cells, fhRPE) that does not normally accumulate lipofuscin and A2E. Then exogenous retinoids were supplied and the subsequent accumulation of lipofuscin and retinoids was followed after extraction by fluorescence or HPLC/MS/MS.
The data show that lipofuscin correlates well with clinical observations but there is little correlation between A2E and lipofuscin. Neither age nor clinical diagnosis of dry- or wet-AMD changed the peripheral distribution of A2E and other bis-retinoids. From phosphatidyl choline vesicles, fhRPE cells took up and metabolized vitamin-A and all-trans retinal, however, bis-retinoids were not generated. From phosphatidyl-ethanolamine containing vesicles the generation of bis-retinoid precursors was observed. Feeding the cells with bleached rod outer segments also resulted in the generation of lipofuscin and bis-retinoids.
The spatially inverse relationship of lipofuscin fluorescence and A2E in the human eye implies that the retinoid and retinoid adduct metabolism varies with the topography of the eye. However, it is still not clear whether A2E and lipofuscin accumulate differently or if A2E is metabolized where lipofuscin is most intense. The model system experiments are the first steps to understand the link between retinoids and observed patterns of AMD. Elucidating this link is essential for eliminating only the toxic components of lipofuscin instead of inhibiting the entire visual cycle.
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