An in silico model of retinal cholesterol dynamics (RCD model): insights into the pathophysiology of dry AMD

Abstract

We developed an in silico mathematical model of retinal cholesterol (Ch) dynamics (RCD) to quantify the physiological rate of Ch turnover in the rod outer segment (ROS), the lipoprotein transport mechanisms by which Ch enters and leaves the outer retina, and the rates of drusen growth and macrophage-mediated clearance in dry age-related macular degeneration. Based on existing experimental data and mechanistic hypotheses, we estimated the Ch turnover rate in the ROS to be 1–6 pg/mm2/min, dependent on the rate of Ch recycling in the outer retina, and found comparable rates for LDL receptor-mediated endocytosis of Ch by the retinal pigment epithelium (RPE), ABCA1-mediated Ch transport from the RPE to the outer retina, ABCA1-mediated Ch efflux from the RPE to the choroid, and the secretion of 70 nm ApoB-Ch particles from the RPE. The drusen growth rate is predicted to increase from 0.7 to 4.2 μm/year in proportion to the flux of ApoB-Ch particles. The rapid regression of drusen may be explained by macrophage-mediated clearance if the macrophage density reaches ∼3,500 cells/mm2. The RCD model quantifies retinal Ch dynamics and suggests that retinal Ch turnover and recycling, ApoB-Ch particle efflux, and macrophage-mediated clearance may explain the dynamics of drusen growth and regression.