Subtle retinal degeneration in pigmented Abca4−/− Rdh8−/− mice

Abstract

Stargardt disease type 1 is a genetic retinal disorder caused by mutations in the ABCA4 gene, leading to toxic bisretinoid accumulation in the retinal pigment epithelium (RPE). This study examines the retinal phenotype of Abca4^−/− Rdh8^−/− double knockout mice on a C57BL/6J background, excluding confounding variants such as the Rpe65 Leu450Met variant or the rd8 mutation in the Crb1 gene, to define the effect of combined Abca4 and Rdh8 deficiency.

Double knockout mice—confirmed free of the rd8 mutation and to not carry the protective Met variant of the Rpe65 gene—were analyzed at 4 and 9 months and compared to Rdh8^−/− single knockouts under varying light exposure. Histological assessments included RPE autofluorescence, morphometric parameters of microglial activation, and retinal layer integrity.

At 4 months, no significant structural differences were observed between genotypes. By 9 months, Abca4^−/− Rdh8^−/− mice showed increased RPE autofluorescence, consistent with elevated bisretinoid accumulation. Four-fold enhanced light exposure affected microglial morphology, and a modest age-related thinning of retinal layers was noted in double knockouts.

In conclusion, increased RPE autofluorescence was confirmed in Abca4^−/− Rdh8^−/− mice on the C57BL/6J background, but only mild retinal structural and inflammatory changes were observed. The severe early-onset degeneration reported in prior studies was not replicated, likely due to the absence of the rd8 mutation present in the double knockout mouse strain at its original description. This suggests that the rd8 mutation drove neurodegeneration, while the combined Abca4 and Rdh8 deficiency alone is comparatively well tolerated in the murine retina.