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Steven C. McLoon, Victoria Rogness; Bexarotene blocks the pathogenic effects of amyloid-β oligomers on RPE cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2444.
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Oligomers of amyloid-β (Aβ) are a major component of drusen in patients with age-related macular degeneration (AMD). Aβ oligomers may result in changes in the retinal pigment epithelium (RPE) that ultimately lead to AMD. Aβ oligomers are pathogenic in Alzheimer’s disease. Over 100 drugs have shown promise in animal models of Alzheimer’s disease, yet none of these were effective in human trials. The problem may be that Alzheimer’s disease is detected clinically only after there is significant neurodegeneration. AMD, on the other hand, can be detected very early in the course of the disease. If Aβ oligomers are pathogenic in AMD, then drugs that showed promise for treating Alzheimer’s may be a potential treatment for AMD. We asked whether one of these drugs, bexarotene, can block the pathogenic effects of Aβ oligomers on RPE cells.
Mono-layer cultures of differentiated ARPE19 cells, a human RPE cell line, were treated with synthetic oligomerized Aβ (1-42) with or without bexarotene. Bexarotene facilitates Aβ clearance, and ameliorated symptoms in a mouse model of Alzheimer’s disease. Bexarotene has FDA approval for use in clinical conditions unrelated to neurodegenerative diseases, and has minimal side-effects in humans. The treated cells were monitored over a period of 12 days.
Aβ oligomers resulted in a dose-dependent disorganization of the RPE cells. This was apparent by phase contrast microscopy as scattered clumps of cells by three days after the start of treatment, and got progressively worse over the course of the experiment. Immunohistochemistry revealed a loss of ZO1+ junctional complexes between cells. Bexarotene prevented the loss of the junctional complexes and reduced the cell clumps. A calcein/ethidium homodimer based live/dead assay showed that Aβ oligomers resulted in dose-dependent cell death beginning six days after the start of treatment. With the highest dose of Aβ, bexarotene reduced cell death by over half, and at lower doses of Aβ, it prevented the cell death. Western blot analysis showed that Aβ initiated an accumulation of Aβ oligomers by the cells, which was prevented by bexarotene.
Bexarotene reduced the negative effects of Aβ oligomers on cultured RPE cells. This suggests that bexarotene may be efficacious for treatment of AMD clinically.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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