期刊
AGING CELL
卷 8, 期 2, 页码 162-177出版社
WILEY
DOI: 10.1111/j.1474-9726.2009.00456.x
关键词
aging; degeneration; oxidative stress; retina; tight junction
资金
- EVI-GenoRET [LSHG-CT-2005-512036]
- RETINA France
- Ministere de la Recherche
- FEdEration des Aveugles et HandicapEs Visuels de France
- Agence Nationale de la Recherche Scientifique (ANR)
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 (A beta) 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 A beta(1-42) - OA beta(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 OA beta(1-42) on mitochondrial redox potential and transepithelial permeability. Subretinally injected OA beta(1-42) induced pigmentation loss and RPE hypertrophy but not RPE cell apoptosis in C57BL/6 J mice. Rapid OA beta(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 A beta in RPE alterations and dysfunctions leading to retinal degeneration and suggests that targeting A beta may help develop selective methods for treating diseases involving retinal degeneration, such as AMD.
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