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Seyedeh Maryam Zekavat, James Lu, Cyrille Maugeais, Norman Mazer; In-silico model of retinal cholesterol dynamics: Insights into the pathophysiology of dry AMD. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3987.
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AMD is the leading cause of blindness in the elderly and begins with the currently un-treatable “dry form,” characterized by cholesterol (Ch) deposits beneath the retinal pigment epithelium (RPE). To better understand the normal physiology of retinal Ch dynamics (RCD) and the pathophysiology of dry AMD, we developed a novel in-silico model based on a quantitative analysis of literature data and mechanistic hypotheses of RCD.
Our model (Figure) uses a transit-chain to represent the turnover and recycling of Ch in Rod Outer Segment (ROS) discs; permeability coefficients (P1 and P2) to characterize transcytosis of LDL across the choroid; Michaelis-Menten (MM) kinetics to describe LDL-receptor mediated Ch uptake by the RPE; mass-balance for the rate of Ch deposition in Bruch’s membrane (BrM); and MM kinetics for the rate of macrophage-mediated removal of Ch deposits (via ABCA1/ApoA-I). Calculations are made using MATLAB.
Based on the shedding rate of ROS discs, their Ch content and the rod density, we calculate that the retinal Ch turnover rate will range from 1 pg/min/mm^2 retina (complete Ch recycling) to 6 pg/min/mm^2 retina (no Ch recycling). From in-vitro studies of LDL transcytosis across capillary endothelia, we estimate P1 to be ~1x10^-7 cm/sec, which is sufficient to allow LDL-receptor-mediated uptake by the RPE to provide Ch at a rate comparable to the estimated Ch turnover in the ROS. Assuming that the rate of Ch secretion from RPE to BrM is equal to the estimated turnover rate in the retina, and that the secreted Ch is retained in the BrM, the thickness of the deposited Ch layer is calculated to increase by 0.7 - 4.2 um per year, consistent with the slow formation of drusen over decades. Finally, the rate at which deposited Ch can be removed by macrophages is proportional to their density in the BrM. Assuming 10,000 macrophages/mm^2, a 125 um-thick druse could be cleared in ~10 months, consistent with the maximum rates observed in OCT studies.
Our model suggests that retinal Ch turnover in the ROS is central to understanding the normal physiology of RCD and the slow rate of Ch deposition in dry AMD. Our model also suggests that the Ch removal rate in drusen is consistent with macrophage-mediated ABCA1/ApoA-1 transport. Further data would be useful to support and test these concepts.
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