Age-related maculopathy (ARM) is the leading cause of untreatable vision loss among the elderly in Western society. Early ARM features poorly understood fatty deposits under the retina. We propose that: ARM, like atherosclerotic cardiovascular disease, involves local cellular response to the retention of an apolipoprotein (apo) B-containing lipoprotein in a vascular intima, with the twist that the apoB-containing lipoprotein derives from retinal pigment epithelium (RPE). We show that esterified cholesterol and 80-100 nm solid particles are present in normal aged Bruch's membrane (BrM), drusen and basal deposits contain cholesterol and apoB, and the RPE contains mRNA and protein for apoB and microsomal triglyceride transfer protein (MTTP), the hallmark of a lipoprotein secreting cell. Perturbation of a constitutive RPE lipoprotein pathway is a plausible mechanism for the formation of cholesterol-enriched lesions. A plausible function for an RPE lipoprotein is to clear fatty acids from phagocytosed photoreceptor outer segments. Our first priority is proving that an RPE lipoprotein pathway exists and learning its normal function. In human eyes, we will describe lipoprotein particles in isolated drusen and in BrM, using electron microscopy, immunohistochemistry, density gradient ultracentrifugation, and enzymatic lipid assays. In cultured ARPE-19 cells, we will determine the optimal method for lipid-loading so that the components of secreted particles can be characterized chemically and ultrastructurally, and we will determine the effect of modulating MTTP activity on RPE lipoprotein assembly and secretion in vitro. In mice, we will study the effect of systemic administration of specific and potent inhibitors of MTTP on the formation of intracellular oil droplets in RPE following photoreceptor phagocytosis in normal and bright light. Our results will be valuable in assessing the extent which ARM and atherosclerotic cardiovascular disease share mechanisms with regard to extracellular lipoprotein accumulation and the cell biology of lipoprotein secreting cells. This information is required to determine if treatments that modify hepatic lipoprotein production should be considered for treating early ARM. ? ?
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