Pilgrim, Matthew; (2018) High-resolution imaging and molecular analysis of sub-retinal pigment epithelial deposits associated with age-related macular degeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Drusen and Basal linear deposits are hallmark features of early and intermediate age-related macular degeneration (AMD). These extracellular deposits accumulate between the basal lamina of the RPE and the inner collagenous layer of Bruch’s membrane. They contain proteins, lipids, trace metals and mineral constituents. While early AMD is not typically accompanied with vision loss, it is likely to initiate the pathological processes leading to blindness in the elderly. Understanding how early stage AMD is initiated could enable the development of novel treatment strategies that might delay/prevent progression to advanced AMD and vision loss. It was hypothesized that mineral deposition in the sub-RPE space directly mediates extracellular deposit formation followed by AMD progression. Using high-resolution molecular imaging modalities including electron microscopy, energy dispersive x-ray spectroscopy, time of flight-secondary ion mass spectrometry, and synchrotron x-ray fluorescence spectroscopy, in addition to electron and synchrotron x-ray diffraction studies, the mineral constituents involved in biomineralization events leading to deposit formation were investigated. Here, clinically significant information regarding sub-RPE deposit formation is reported. Extracellular deposits were found to contain either magnesium(Mg)-substituted whitlockite spherules (~1.3 µm diameter) or large hydroxyapatite nodules without Mg (up to 100 µm diameter). The latter was identified as a progression biomarker for GA. The absence of detectable Mg in nodules suggests that modification of Mg availability in the sub-RPE space might influence progression to late AMD. Moreover, analysis of a primary RPE culture model demonstrated that RPE cells could form deposits containing all of the major constituents of drusen, including hydroxyapatite. Therefore, this model provides a platform for investigating the underlying mechanisms of sub-RPE deposit formation in addition to testing novel treatment strategies. The work presented in this thesis gives a new perspective on sub-RPE deposit biogenesis and suggests that inorganic chemistry and materials science approaches might be informative for future studies.

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