Amyloid-beta(1-42) alters structure and function of retinal pigmented epithelial cells.
Age-related macular degeneration (AMD) is characterized by the formation of drusen, extracellular deposits associated with atrophy of the retinal pigmented epithelium (RPE), disturbance of the transepithelial barrier and photoreceptor death. Amyloid-beta (Abeta) is present in drusen but its role during AMD remains unknown. This study investigated the in vitro and in vivo effects of the oligomeric form of Abeta(1-42) - OAbeta(1-42) - on RPE and found that it reduced mitochondrial redox potential and increased the production of reactive oxygen species, but did not induce apoptosis in RPE cell cultures. It also disorganized the actin cytoskeleton and halved occludin expression, markedly decreasing attachment capacity and abolishing the selectivity of RPE cell transepithelial permeability. Antioxidant pretreatment partially reversed the effects of OAbeta(1-42) on mitochondrial redox potential and transepithelial permeability. Subretinally injected OAbeta(1-42) induced pigmentation loss and RPE hypertrophy but not RPE cell apoptosis in C57BL/6 J mice. Rapid OAbeta(1-42)-induced disorganization of cytoskeletal actin filaments was accompanied by decreased RPE expression of the tight junction proteins occludin and zonula occludens-1 and of the visual cycle proteins cellular retinaldehyde-binding protein and RPE65. The number of photoreceptors decreased by half within a few days. Our study pinpoints the role of Abeta in RPE alterations and dysfunctions leading to retinal degeneration and suggests that targeting Abeta may help develop selective methods for treating diseases involving retinal degeneration, such as AMD.
Bruban
Julien
J
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris 6, UMR S 872, F-75006 Paris, France.
Glotin
Anne-Lise
AL
Dinet
Virginie
V
Chalour
Naïma
N
Sennlaub
Florian
F
Jonet
Laurent
L
An
Na
N
Faussat
Anne Marie
AM
Mascarelli
Frédéric
F
D000375:Aging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005136:Eye Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008268:Macular Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D005136:Eye Proteins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C075222:amyloid beta-protein (1-42)