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J. Feher, I. Kovacs, C. Mannino, C. Balacco Gabrieli, Ophthalmic Neuroscience Program; Cellular Pathology of the Innate Immunity in Early Age-Related Macular Degeneration. Key for Pathogenic Mechanism and Treatment. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6184.
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To reveal morphologic alterations of endosomes (phagosomes), lysosomes, endoplasmic reticulum (ER) Golgi complex, mitochondria and peroxisomes in the retinal pigment epithelium (RPE) and capillary endothelial cells in normal aging and in early age-related macular degeneration (AMD). These organelles are involved in the renewal of photoreceptor outer segment and at the same time, they are key components of the innate immunity
Sixty-two specimens from human retinas were studied with electron microscopy, histochemistry and morphometry. All specimens were obtained from surgically removed eyes, thus artifacts due postmortem changes were insignificant, as compared to donor eyes. This unique material permitted to reveal initial and previously unknown structural alterations of the involved cells.
Endosomes and lysosomes are the most abundant organelles in the RPE in all studied specimens. Endosomes are formed from distal discs of the photoreceptor outer segments, then fused with the apical plasma membrane and engulfed by the cytoplasm of RPE. Lysosomes, peroxisomes, melanosomes and mitochondria may show close topographic correlations suggesting coordinated functioning. Endosomes may fuse with lysosomes and then may release their substances into the Bruch’s membrane and capillary endothelium. While all cellular organelles decrease significantly with age (p<0,05) endosomes remained unchanged, and their release to Bruch’s membrane is increased as shown by morphometric analysis of both basal infoldings of the RPE (p<0,05) and Bruch’s membrane lipids and glycoproteins (p<0,01). Exocytosis of lysosome derived substances into the Bruch’s membrane may evoke invading cell-processes (‘invasomes’) from the capillary endothelium. Age-related decrease in organelles and increase in Bruch’s membrane alterations were significantly more severe in AMD (p<0,01).
These findings suggested that at least two sequences of subcellular mechanisms of the photoreceptor renewal are identical to those of the innate immune response: (i) catabolism of worn-out disc membrane (phagocytosis, lysosomal digestion, mitochondrial metabolism, exocytosis). (ii) endothelial and macrophage reaction evoked by metabolic by-products deposited in the Bruch’s membrane. We hypothesized that improvement of lysosomal-mitochondrial catabolic pathways in the RPE may be a new target for preventing and treating AMD
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