title: Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells.
abstract: Cellular events responsible for the initiation of major neurodegenerative disorders of the eye leading to blindness, including age-related macular degeneration, Stargardt and Best diseases, are poorly understood. Accumulation of vitamin A dimers, such as N-retinylidene-N-retinylethanolamine (A2E) in the retinal pigment epithelium (RPE), is one of the earliest measurable events preceding retinal degeneration. However, the extent to which these dimers contribute to tissue degeneration is not clear. To determine if A2E could trigger morphological changes associated with the degenerating RPE and subsequent cell death, we evaluated its toxicity to cultured human RPE cells (ARPE-19). We show that A2E triggered the accumulation of debris followed by a protracted death. A2E was up to ≈ 14-fold more toxic than its precursor, retinaldehyde. Measurements reveal that the concentration of A2E in the aged human eye could exceed the concentration of all other retinoids, opening the possibility of A2E-triggered cell death by several reported mechanisms. Findings suggest that accumulation of vitamin A dimers such as A2E in the human eye might be responsible for the formation of ubiquitous RPE debris, an early indication of retinal degeneration, and that preventing or reducing the accumulation of vitamin A dimers is a prudent strategy to prevent blindness.
authors: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032, USA.
authors: D M
authors: DM
authors: Mihai
authors: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032, USA.
authors: I
authors: I
authors: Washington
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016923:Cell Death; D002478:Cells, Cultured; D019281:Dimerization; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D012162:Retinal Degeneration / Q000378:metabolism* / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000378:metabolism; D012172:Retinaldehyde / Q000378:metabolism / Q000633:toxicity; D014801:Vitamin A / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: D014801:Vitamin A; D012172:Retinaldehyde