Transgenic Mice That Express Human Apolipoprotein B100 (ApoB100) in the Retinal Pigmented Epithelium (RPE) and Liver Develop Phenotypic Features of Early Age-Related Macular Degeneration (AMD)

Abstract

Purpose: : AMD is the leading cause of acquired blindness in the United States, but the pathophysiology remains poorly understood. Defining phenotypic features of early AMD include RPE derangement and basal deposit formation in Bruch membrane. A change that occurs prior to basal deposits is the accumulation of ApoB100 lipoprotein particles. The purpose of this study was to determine whether transgenic mice that express human ApoB100 in the RPE-choroid and liver develop landmarks of early AMD over time.

Methods: : Transgenic human ApoB100 mice designated, "ApoB100" mice, and control mice were given a normal chow (n=3 for each group) or high fat diet (n=8, ApoB100; n=12 controls) for 12 months. Plasma total cholesterol, triglyceride, and free fatty acids were determined with enzymatic kits. Mice were evaluated for human ApoB100 mRNA in the RPE-choroid and liver by RT-qPCR. Phenotypic changes associated with early AMD were determined via ultrastructural analysis using TEM, and changes were semi-quantified using linear regression analysis.

Results: : Both the RPE-choroid and liver of ApoB100 mice expressed human ApoB100. TEM revealed ultrastructural changes consistent with early human AMD including loss of basal infoldings and accumulation of cytoplasmic vacuoles in RPE cells as well as basal laminar deposits containing heterogeneous debris in Bruch membrane. While none of the ApoB100 mice on a normal chow diet or wild type mice of either diet developed basal linear deposits, nearly 50% of the ApoB100 mice given a high fat diet developed this deposit. Regression analysis showed that genotype (human ApoB100 transgene) was a stronger influencing factor than high fat diet in producing AMD-like lesions.

Conclusions: : Transgenic human ApoB100 mice develop validated phenotypic changes that are seen in early AMD. Future studies will take advantage of this model to uncover the role that ApoB100 lipoproteins might play in triggering the onset of AMD.

Keywords: age-related macular degeneration • retinal pigment epithelium • lipids