Author: Jennifer C. Tournear

Publisher:

Published: 2018

Total Pages: 238

ISBN-13: 9780438392229

Age-related macular degeneration (AMD) is a retinal disease that can cause severe vision loss. It is responsible for the majority of blindness in developed countries in the elderly population. The disease is characteristically multifactorial where oxidative stress, inflammation and retinal lipofuscin (cellular waste product) accumulation have been indicated in disease progression. The retinal pigment epithelial (RPE) attaches to the Bruch's membrane (BM) and the symbiotic relationship between these two layers of the retina is essential for the visual cycle to function normally. Retinal lipofuscin is believed to contribute to drusen (characteristic deposits in the AMD BM) that negatively impact the BM and, in turn, the retina. Investigating the biological changes to the retina that are catalyzed by chemical reactions, such as photooxidation, can help to further the understanding of AMD. It is believed that when the BM is significantly modified, the RPE cells detach and undergo cell death. Retinal cell death is a hallmark of AMD. This work includes the investigation of ARPE-19 cell death when extracellular matrix (ECM) has been modified to model AMD through oxidative stress, aging and inflammation. Results indicate overlapping cell death pathways are activated as a result of ECM modification including proinflammatory cell death mechanisms: pyroptosis and necroptosis. Lipofuscin extracts obtained from human donor eyes where donors were previously diagnosed with one of three retinal diseases (wet AMD, dry AMD or diabetic retinopathy) are investigated using liquid chromatography mass spectrometry. Photooxidation products, inflammatory biomarkers and aging biomarkers are investigated as being components making up lipofuscin. Specifically, the observation of these components in association with a particular retinal disease is examined. Results indicate trends associated with oxidative stress markers being linked to wet AMD samples and inflammatory biomarkers being mostly associated with dry AMD samples. This work uses a two-prong approach to explore AMD onset and progression. Through the investigation of cell death using disease models and the components of lipofuscin buildup in human tissue, we begin to identify the impact and consequences these biological changes have on the retina.