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S. C. Finnemann, E. F. Nandrot, A. K. Shirazi; Anti-Oxidants Prevent Age-Related Blindness and Lipofuscin Caused by Lack of Diurnal RPE Phagocytic Rhythm in Mice Lacking vβ5 Integrin. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1535.
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Cumulative oxidative damage of the retinal pigment epithelium (RPE) layer of the retina causes formation of pro-oxidant lipofuscin and contributes to RPE dysfunction and atrophy in dry AMD. We previously showed that photoreceptor function (but not viability) in β5 integrin null mice dramatically declines with age. In these mice, lack of αvβ5 integrin receptors disrupts RPE signaling pathways abolishing the diurnal peak of RPE phagocytosis of shed outer segment fragments. As a consequence of this primary phagocytic defect, β5 integrin null mice develop age-related blindness and accumulate excess autofluorescent granules in the RPE. Here, we test whether such age-related dysfunction of β5 integrin null retina is associated with oxidative damage and whether it can be averted by increasing anti-oxidant intake.
We quantified protein carbonyl content and lipid peroxidation to assess age-related oxidative changes in retina and RPE of β5 integrin null and wild-type mice. We increased dietary intake of anti-oxidants by test groups of mice and compared their retinal changes with age to changes in control groups fed placebo. We monitored food intake and weight of animals. We tested visual function of mice monthly by recording corneal scotopic electroretinograms (ERGs). We monitored autofluorescent lipofuscin and RPE phagosome load as a function of time of day by fluorescence and light microscopy of fixed eye tissue.
Both protein and lipid components in β5 integrin null eyes acquired significantly higher levels of oxidative modifications with age than wild-type eyes. Oxidative modifications localized to both RPE and neural retina. Dietary supplementation with anti-oxidants did not change food intake, longevity, weight, or general appearance of mice. As expected, anti-oxidants had no effect on the primary defect of β5 integrin null RPE: regardless of diet, β5 integrin null RPE lacked the diurnal peak of phagocytosis that is characteristic for wild-type RPE. In contrast, increasing dietary intake of anti-oxidants was sufficient to largely prevent retinal oxidative damage and age-related decline in ERG a-wave amplitudes in β5 integrin null mice.
We conclude that oxidative processes cause retinal dysfunction secondary to the constitutive loss of phagocytic rhythm in β5 integrin null mice. Moreover, our exciting data demonstrate that dietary supplementation with anti-oxidants can be sufficient to prevent age-related vision loss.
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