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Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration.

Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH - PLoS ONE (2009)

Bottom Line: Furthermore, these markers are also found in the region of Bruch's membrane in old mice.By in vitro modeling increased mtDNA damage induced by rotenone, an inhibitor of mitochondrial complex I, in the RPE, we found that the phagocytic activity was not altered but that there were: 1) increased autophagic markers, 2) decreased lysosomal activity, 3) increased exocytotic activity and 4) release of chemoattractants.Molecular and cellular changes in the old RPE may underlie susceptibility to genetic mutations that are found in AMD patients and may be associated with the pathogenesis of AMD in the elderly.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Forsythe Laboratory for the Investigation of the Aging Retina, Northwestern University School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Age-related macular degeneration (AMD) is a major cause of loss of central vision in the elderly. The formation of drusen, an extracellular, amorphous deposit of material on Bruch's membrane in the macula of the retina, occurs early in the course of the disease. Although some of the molecular components of drusen are known, there is no understanding of the cell biology that leads to the formation of drusen. We have previously demonstrated increased mitochondrial DNA (mtDNA) damage and decreased DNA repair enzyme capabilities in the rodent RPE/choroid with age. In this study, we found that drusen in AMD donor eyes contain markers for autophagy and exosomes. Furthermore, these markers are also found in the region of Bruch's membrane in old mice. By in vitro modeling increased mtDNA damage induced by rotenone, an inhibitor of mitochondrial complex I, in the RPE, we found that the phagocytic activity was not altered but that there were: 1) increased autophagic markers, 2) decreased lysosomal activity, 3) increased exocytotic activity and 4) release of chemoattractants. Exosomes released by the stressed RPE are coated with complement and can bind complement factor H, mutations of which are associated with AMD. We speculate that increased autophagy and the release of intracellular proteins via exosomes by the aged RPE may contribute to the formation of drusen. Molecular and cellular changes in the old RPE may underlie susceptibility to genetic mutations that are found in AMD patients and may be associated with the pathogenesis of AMD in the elderly.

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Immunolocalization of autophagy marker, Atg5, in the human RPE/choroid.In these confocal immunofluorescence images: an-anti-Atg5 antibody labels particles in drusen (arrows). (A) AMD eye from 94-year-old male; (B) AMD eye from 97-year-old male; (C) AMD eye from 74-year-old male; (D) non-AMD eye from 75-year-old male ; (E) non-AMD eye from 60-year-old male; (F) non-AMD eye from 87-year-old male. Dr, drusen. Scale bar = 20 µm. Blue: DAPI; red: Atg-5; Green: autofluorescence.
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pone-0004160-g001: Immunolocalization of autophagy marker, Atg5, in the human RPE/choroid.In these confocal immunofluorescence images: an-anti-Atg5 antibody labels particles in drusen (arrows). (A) AMD eye from 94-year-old male; (B) AMD eye from 97-year-old male; (C) AMD eye from 74-year-old male; (D) non-AMD eye from 75-year-old male ; (E) non-AMD eye from 60-year-old male; (F) non-AMD eye from 87-year-old male. Dr, drusen. Scale bar = 20 µm. Blue: DAPI; red: Atg-5; Green: autofluorescence.

Mentions: We found that Atg5, an autophagy marker, was present in drusen in the retina of normal old eyes and old eyes with AMD. The distribution of Atg5 was assessed in the eyes of ten donors (twelve eyes) with AMD and six donors of similar age (twelve eyes) without AMD (representative samples are shown in Fig. 1). In donors with AMD, a cluster of Atg5 immunoreactivity was present in the large drusen found in the sub-RPE space (Fig. 1 A–C, three different donors). In age-matched eyes without AMD, Atg5 was present as small isolated spots in drusen and the sub-RPE space (D–F, three different donors).


Autophagy and exosomes in the aged retinal pigment epithelium: possible relevance to drusen formation and age-related macular degeneration.

Wang AL, Lukas TJ, Yuan M, Du N, Tso MO, Neufeld AH - PLoS ONE (2009)

Immunolocalization of autophagy marker, Atg5, in the human RPE/choroid.In these confocal immunofluorescence images: an-anti-Atg5 antibody labels particles in drusen (arrows). (A) AMD eye from 94-year-old male; (B) AMD eye from 97-year-old male; (C) AMD eye from 74-year-old male; (D) non-AMD eye from 75-year-old male ; (E) non-AMD eye from 60-year-old male; (F) non-AMD eye from 87-year-old male. Dr, drusen. Scale bar = 20 µm. Blue: DAPI; red: Atg-5; Green: autofluorescence.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2612751&req=5

pone-0004160-g001: Immunolocalization of autophagy marker, Atg5, in the human RPE/choroid.In these confocal immunofluorescence images: an-anti-Atg5 antibody labels particles in drusen (arrows). (A) AMD eye from 94-year-old male; (B) AMD eye from 97-year-old male; (C) AMD eye from 74-year-old male; (D) non-AMD eye from 75-year-old male ; (E) non-AMD eye from 60-year-old male; (F) non-AMD eye from 87-year-old male. Dr, drusen. Scale bar = 20 µm. Blue: DAPI; red: Atg-5; Green: autofluorescence.
Mentions: We found that Atg5, an autophagy marker, was present in drusen in the retina of normal old eyes and old eyes with AMD. The distribution of Atg5 was assessed in the eyes of ten donors (twelve eyes) with AMD and six donors of similar age (twelve eyes) without AMD (representative samples are shown in Fig. 1). In donors with AMD, a cluster of Atg5 immunoreactivity was present in the large drusen found in the sub-RPE space (Fig. 1 A–C, three different donors). In age-matched eyes without AMD, Atg5 was present as small isolated spots in drusen and the sub-RPE space (D–F, three different donors).

Bottom Line: Furthermore, these markers are also found in the region of Bruch's membrane in old mice.By in vitro modeling increased mtDNA damage induced by rotenone, an inhibitor of mitochondrial complex I, in the RPE, we found that the phagocytic activity was not altered but that there were: 1) increased autophagic markers, 2) decreased lysosomal activity, 3) increased exocytotic activity and 4) release of chemoattractants.Molecular and cellular changes in the old RPE may underlie susceptibility to genetic mutations that are found in AMD patients and may be associated with the pathogenesis of AMD in the elderly.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Forsythe Laboratory for the Investigation of the Aging Retina, Northwestern University School of Medicine, Chicago, Illinois, United States of America.

ABSTRACT
Age-related macular degeneration (AMD) is a major cause of loss of central vision in the elderly. The formation of drusen, an extracellular, amorphous deposit of material on Bruch's membrane in the macula of the retina, occurs early in the course of the disease. Although some of the molecular components of drusen are known, there is no understanding of the cell biology that leads to the formation of drusen. We have previously demonstrated increased mitochondrial DNA (mtDNA) damage and decreased DNA repair enzyme capabilities in the rodent RPE/choroid with age. In this study, we found that drusen in AMD donor eyes contain markers for autophagy and exosomes. Furthermore, these markers are also found in the region of Bruch's membrane in old mice. By in vitro modeling increased mtDNA damage induced by rotenone, an inhibitor of mitochondrial complex I, in the RPE, we found that the phagocytic activity was not altered but that there were: 1) increased autophagic markers, 2) decreased lysosomal activity, 3) increased exocytotic activity and 4) release of chemoattractants. Exosomes released by the stressed RPE are coated with complement and can bind complement factor H, mutations of which are associated with AMD. We speculate that increased autophagy and the release of intracellular proteins via exosomes by the aged RPE may contribute to the formation of drusen. Molecular and cellular changes in the old RPE may underlie susceptibility to genetic mutations that are found in AMD patients and may be associated with the pathogenesis of AMD in the elderly.

Show MeSH
Related in: MedlinePlus