| Aim: To define pathological features of photoreceptor and RPE death induced by genetic deficient and blue light irradiation in Abca4-/- mice.
Methods: Albino Abca4 +/+ and Abca4 -/- mice, with homozygous of a Leu-450 allele of RPE65at age 2-13 months were used. Superior retina above optic nerve head (ONH) in right eye was exposed to blue light at 50mW/cm2 for 30 minutes. At day 7 post irradiation, globes were enucleated and processed serial paraffin sections. Retinal outer nuclear layer (ONL) thickness measurement and RPE nuclei counting were performed at digital images of whole retina from 0.2-2.6 mm superior and inferior to ONH, by Leica Microsystems. Bisretinoids in eyecups was analyzed by HPLC.
Results: A progressive thinner of ONL thickness in central retina was revealed significantly (p<0.05) in Abca4-/- mice compared to Abca4 +/+ mice, a 15-20% deduction at 8-9 months, a 23-36% at 11 months and a 54-69% in superiorly and 48-62% inferiorly at 13 months. Blue light-induced Photoreceptor loss is pronounced in Abca4-/- than Abca4 +/+ mice. Comparison of irradiated and non-irradiated eyes in Abca4 -/- mice, statistical significant differences in ONL thickness (p<0.05) was revealed by a 46-69% deduction at 5 months, 24-39% at 8 months, 17-37% at 2 months, and 20-37.6% at 13 months; While in Abca4 +/+ mice, the ONL thickness reduction was obtained significantly (p<0.05) only at 5 months (7.2-14.8%), 8 months (8.3-17.7%) and 12 months (13.9-23.3%).
RPE nuclei loss-induced by blue light irradiation was revealed significantly in all groupsof Abca4 -/- (p<0.001) and Abca4 +/+ mice (p<0.05-0.01) relative to non-irradiated eyes. A wider RPE damaged area was clearly seen histopathologically in Abca4 -/- than Abca4 +/+ mice, but statistical significant difference was obtained only at age of 5 months (p<0.05).
Bisretinoids analysis: Total atRAL-dimer was increased in Abca4 -/-micefrom 2 months (p<0.05), peak at 5 months (p<0.001) and slightly decreased at 8 months (p<0.01) compared to Abca4 +/+ mice. Total A2E are significantly accumulated in Abca4 -/- mice starting at age 4 months (p<0.01), peak at 5-8 months (p<0.001) when compared to age-matched Abca4 +/+ mice.
Conclusions: We provide new insights into Abca4-/- mouse model of Stargardt disease: (1) Abca4 -/- model displays an age-related retinal degeneration phenotype and is associated with atRAL-dimer accumulation in photoreceptors along with aging; (2) RPE death is triggered by blue light irradiation and aggravated with excessive accumulation of A2E in RPE of Abca4 -/-mice. | 
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