Role of Oxidative Stress in Aging of the Retina in the ApoB100,LDLR-/- Mouse, a Murine Model of Aging of the Human Retina

Abstract

Purpose: : Aging is associated with accumulation of lipids at the basement of the retina that may contribute to the development of age-related macular degeneration (AMD), the leading cause of blindness after 60 years of age in Western populations. The ApoB₁₀₀,LDLR^-/- mouse is a relevant model for aging of the Human retina since it shows accumulation of lipids in the retina and impairment of the retinal function. Nevertheless, these features of aging do not inevitably lead to AMD. Other factors may accelerate the processes of aging and lead to retinal degeneration. Among them oxidative stress may be the leading one. The purpose of our work was to establish whether oxidative stress may worsen the signs of aging in the retina of the ApoB₁₀₀,LDLR^-/- mouse.

Methods: : Enhanced oxidative stress was induced in either control or ApoB₁₀₀,LDLR^-/- mice by daily sub-cutaneous injections of D-galactose (D-gal, 50mg/kg body weight) or saline as a control alone or in combination with 24h-exposure to intensive light (2500 lux, 3 times per week) during 8 weeks. Single flash electroretinograms were obtained under scotopic conditions. Accumulation of autofluorescent material in fundus of the animals was assessed by 488nm-imaging using cSLO. Deposition of free cholesterol and esters in the retina was evaluated by epifluorescence microscopy in eye cryosections using filipin staining. Induction of pro-angiogenic gene expression was evaluated by qPCR focusing on VEGF isoforms and receptors.

Results: : Our results suggest a drastic loss of retinal functionality in ApoB₁₀₀,LDLR^-/- mice submitted to oxidative stress: reduction of scotopic b-wave and a-wave amplitudes, increase of a-wave latency. These features were associated with enhanced deposition of autofluorescent material in fundus and cholesteryl esters within the retina of ApoB₁₀₀,LDLR^-/- mice stressed with D-gal and light. Furthermore, there was a trend towards an increase of over-expression of pro-angiogenic factors such as VEGF188 in ApoB₁₀₀,LDLR^-/- mice stressed with D-gal and light.

Conclusions: : Oxidative stress is a promoting factor of aging of the retina that in ApoB₁₀₀,LDLR^-/- mouse may correspond to the threshold at which aging turns into early AMD.

Keywords: aging • oxidation/oxidative or free radical damage • retina