Figure 5.

Lipid cycling pathways leading to soft drusen and an atherosclerosis-like progression in the sub-retinal pigment epithelium basal lamina space. BLinD/soft drusen and SDD are localized external and internal to the RPE, respectively. Normal-aging RPE is at the left and center. AMD is at right. Shown are RPE-based lipid recycling pathways for rods and cones that could drive formation of AMD extracellular lesions. (1) Plasma LDL and HDL delivering lipophilic essentials, including vitamins E, A, lutein, and cholesterol (UC), enter basolateral RPE via LDL receptor and scavenger receptors BI and BII, respectively. (2) ApoB, E lipoproteins secreted basolaterally by RPE (gold circles) are assembled from multiple lipid sources. Fatty acids are dominated by linoleate, implicating internalized plasma lipoproteins (from step 1) as a major source, plus UC from all sources esterified to EC. (3) Lipoproteins retained by binding to BrM extracellular matrix accumulate throughout adulthood (perhaps in concert with less efficient transport by aged choriocapillaries), creating pre-BLinD between the RPE-BL and the inner collagenous layer of BrM. (4) Lipoproteins degrade, fuse, and form lipid pools within BLinD/soft drusen, making them biomechanically fragile, proinflammatory, and cytotoxic. (5) Disks in rod OS lose UC and gain docosahexaenoate in transit from OS base to tip (shown as loss of white). OS-derived docosahexaenoate stored as triacylglycerol in RPE after phagocytosis return to OS. The mechanism of transfer is unknown but could be familiar proteins like interphotoreceptor retinoid-binding protein or hypothetical HDL particles cycling between RPE and photoreceptors, especially under rod-rich perifovea, where subretinal drusenoid deposit forms. (6) Cone OS maintain high-UC content along their length, because their disks are comb-like projections of plasma membrane. Cone OS UC enters RPE via disk shedding, lysosomal uptake, and acid lipase activity. UC is released for intracellular transfer, esterification, and assembly into basolaterally secreted lipoproteins, especially under cone-rich fovea. Reprinted with permission from Pikuleva IA, Curcio CA. Cholesterol in the retina: the best is yet to come. Prog Ret Eye Res. 2014;41:64–89. Copyright © 2014 Elsevier Ltd.