Abstract
The largest risk factor for age-related macular degeneration (ARMD) is advanced age. With aging, there is a striking accumulation of neutral lipids in Bruch's membrane (BrM) of normal eye that continues through adulthood. This accumulation has the potential to significantly impact the physiology of the retinal pigment epithelium (RPE). It also ultimately leads to the creation of a lipid wall at the same locations where drusen and basal linear deposit, the pathognomonic extracellular, lipid-containing lesions of ARMD, subsequently form. Here, we summarize evidence obtained from light microscopy, ultrastructural studies, lipid histochemistry, assay of isolated lipoproteins, and gene expression analysis. These studies suggest that lipid deposition in BrM is at least partially due to accumulation of esterified cholesterol-rich, apolipoprotein B-containing lipoprotein particles produced by the RPE. Furthermore, we suggest that the formation of ARMD lesions and their aftermath may be a pathological response to the retention of a sub-endothelial apolipoprotein B lipoprotein, similar to a widely accepted model of atherosclerotic coronary artery disease (Tabas, I., K. J. Williams, and J. Borén. 2007. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 116:1832-1844). This view provides a conceptual basis for the development of novel treatments that may benefit ARMD patients in the future.
Highlights
TO OUTER RETINA AND CHOROID, STATEMENT OF PURPOSEEmbryologically part of the central nervous system, the retina (Fig. 1A, B) converts light energy to an electrochemical signal for transmission to the brain through the optic nerve
The conceptual framework, borrowed heavily from decades of atherosclerosis research, provides a wide knowledge base and sophisticated clinical armamentarium that can be readily exploited for the ultimate benefit of age-related macular degeneration (ARMD) patients
The goal of new therapeutic approaches for ARMD may be best served by a comprehensive understanding of the retinal pigment epithelium (RPE) as a polarized secretor of lipoproteins
Summary
Epidemiology and risk factors The macula, required for high-acuity vision, is vulnerable to ARMD [25]. The choriocapillaris may be gradually blocked by their own age-related accumulation in BrM, eventually filling this tissue and resulting in a new layer caused by the backward accumulation of these particles toward the RPE Once this lipid wall begins to form between the inner collagenous layer and the RPE basal lamina, more lipids preferentially fill this potential space, leading to the formation of BlinD, which is linear because of the geometry of the space containing it. In a striking parallel with apoBlipoprotein-instigated disease in arterial intima, the RPE/ BrM complex in aging and ARMD exhibits accumulation of oxidized lipoproteins, different forms of cholesterol, lipid-rich and structurally unstable lesions, and inflammation-driven downstream events. One model invokes the opposing effect of cellular cholesterol export from RPE into BrM and from macrophages into intima to explain the opposite direction of apoE4’s influence in ARMD and CAD [24]
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