Amin, Sepideh; (2003) Sub-retinal pigment epithelial deposits in ageing and age-related macular degeneration: In vitro and in vivo observations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness in the developed world. It is a degenerative disorder affecting the central retina in those over 50 years of age. Little is known about the pathogenesis of this condition and environmental and / or genetic factors are likely to play a role. In donor eyes of AMD patients, deposits under the retinal pigment epithelium (RPE), the supporting layer of the retina, are a frequent finding. These deposits can vary extensively, both in their composition and structure. The role of sub-RPE deposits in the pathogenesis of AMD is largely unknown. They have however, been implicated as either the cause or the consequence of AMD. The aim of this body of work is to increase the understanding of AMD pathogenesis, by examining these conspicuous deposits. Work was carried out in 2 areas; the first involved the assessment of the importance of sub-RPE deposits in AMD as compared to ageing and the second involved the creation of a in vitro model of sub-RPE deposit formation. 1. Sub-retinal deposits were studied in human donor eyes using electron microscopy. Donor eyes were selected from a repository of approximately 2000 pairs of human donor eyes (between 0-102 years of age) obtained from the Mid-America Transplant Unit. Peripheral and macular electron micrographs of donors were examined. These data confirmed the importance of basal laminar deposits and basal linear deposits in both ageing and different subsets of AMD. 2. The in vitro model consisted of growing ARPE-19 cells on collagen type I coated membrane supports or tissue culture plastic. A validated method for analysing these deposits using electron microscopy was also simultaneously developed. Subsequently with a view to manipulating the sub-RPE deposits formed, the composition of the tissue culture media was altered. These experiments showed that sub-RPE deposit formation could be manipulated and the sub-RPE deposits were reduced most dramatically when challenged with metalloproteinases (MMP) 9 and tumour necrosis factor (TNF) α. However, these substances are known to be toxic and this toxicity would limit their clinical use. Future work would be to further understanding of the cellular control of sub-RPE deposit formation with a view to delineating the upstream cellular pathways that correlate with abnormal deposit formation. This could potentially lead to the discovery of new non-toxic agents, which could be used in a clinical setting.

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