Effects of lipofuscin accumulation on lysosomal functions of human RPE cells

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Age-related macular degeneration (AMD) is the leading cause of legal blindness in the industrialized world beyond 50 years of age. Several lines of evidence suggest that ageing changes of the retinal pigment epithelium (RPE) and Bruch's membrane play a key role in the pathogenesis of the disease. In postmitotic RPE cells autofluorescent lipofuscin granules accumulate with age in den lysosomal compartment mainly as a byproduct of constant phagocytosis of membranous discs shed from photoreceptor outer segments. Recently a major retinoid component of human RPE lipofuscin has been identified: N-retinylidene-N-retinylethanolamine (A2-E). In human RPE cell cultures we plan to investigate the effect of A2-E on degradative functions of lysosomes, and to evaluate its mechanism of action. Specific aims include determination of the mechanism of lysosomal enzyme inhibition by A2-E, its influence phagocytic activity at the basal cell side as well as topographic variation of A2-E accumulation. These investigations will be performed not only to better understand the role of lipofuscin accumulation but also to manipulate these mechanisms for both experimental and therapeutic ends.