Retinal phenotype of APOB100 transgenic mice on a Western diet with human-like hyperlipidemia and cholesterol crystals in the retina and choroid

Drusen and subretinal drusenoid deposits, the pathognomonic lesions for age-related macular degeneration (AMD), are rich in cholesterol. Yet, AMD is not consistently linked to plasma lipids. Here wild-type and human apolipoprotein B100-expressing (APOB100) mice were put on a Western type of diet for 13 months and then assessed for plasma lipid profile, high-density lipoprotein (HDL) heterogeneity, status of intraretinal and choroidal vasculatures, retinal structure, function, levels of cholesterol and other sterols, lipid and cholesterol distribution and expression of cholesterol-related genes. The dietary effects were more pronounced in APOB100 mice, which had human-like hyperlipidemia and different subpopulations of HDL₃, than in wild-type mice. In addition, the APOB100 retina showed increased cholesterol input from the systemic circulation, higher cholesterol content, more cholesterol crystals, elevated expression of HDL-related genes, lipid accumulation in the retinal pigment epithelium and Bruch's membrane, and impaired function compared with the wild-type retina. Remarkably, in both genotypes, cholesterol crystals were detected in the choroid, piercing toward Bruch's membrane and leading to macrophage infiltration. Our data indicate how plasma lipid profile could be linked to AMD and that cholesterol crystals in the choroid should be further investigated as contributors to AMD development and progression.