Abstract
Strong evidence suggests that dysregulated lipid metabolism involving dysfunction of the retinal pigmented epithelium (RPE) underlies the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly. A hallmark of AMD is the overproduction of lipid- and protein-rich extracellular deposits that accumulate in the extracellular matrix (Bruch's membrane (BrM)) adjacent to the RPE. We analyzed apolipoprotein A-1 (ApoA-1)-containing lipoproteins isolated from BrM of elderly human donor eyes and found a unique proteome, distinct from high-density lipoprotein (HDL) isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans. We hypothesize that this interaction promotes lipoprotein deposition onto BrM glycosaminoglycans, initiating downstream effects that contribute to RPE dysfunction/death. We tested this hypothesis using two potential therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of RPE cells and aged donor BrM tissue. Second, an ApoA-1 mimetic, 5A peptide, was demonstrated to modulate the composition and concentration of apolipoproteins secreted from primary porcine RPE cells. Significantly, in a mouse model of AMD, this 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes to the protein composition resulting from the high-fat, high-cholesterol diet in this model. Together, these results suggest that targeting HDL interactions with BrM represents a new strategy to slow AMD progression in humans.
Highlights
The proteomic profile of these purified high-density lipoprotein (HDL) samples was examined, and the data showed an increase in several apolipoproteins, including ApoE, ApoB, ApoC-III, and ApoA-IV, associated with the HDL from Bruch’s membrane (BrM) compared with the plasma HDL; this was true for the complement pathway–related proteins C3, clusterin, and vitronectin (Table 1)
Proteome of an isolated macula versus periphery BrM punch and from AMD versus control donor. It is a tenet of the “response to retention” hypothesis of atherosclerosis that ApoB100 and ApoE on lipoproteins from the plasma can interact with the GAGs on the extracellular matrix (ECM) in the arterial wall in the initial stages of the disease [72, 73]. It follows that the increases in ApoB and ApoE found on the human BrMderived HDL would increase its ability to bind to the GAGs on BrM
We show that very-low-density lipoprotein (VLDL) and lowdensity lipoprotein (LDL) containing ApoB and ApoE bind to the retinal pigmented epithelium (RPE) ECM, whereas plasma-derived HDL, which has very low concentrations of ApoB and lower ApoE content compared with BrM-HDL, does not bind to the RPE ECM to the same extent (Fig. 2, A–C)
Summary
We isolated lipoproteins from aged, human donor eye BrM and found that the cholesterol was mainly carried by lipoproteins, which had the same density and size as HDL (Fig. 1). The proteomic profile of these purified HDL samples was examined, and the data showed an increase in several apolipoproteins, including ApoE, ApoB, ApoC-III, and ApoA-IV, associated with the HDL from BrM compared with the plasma HDL; this was true for the complement pathway–related proteins C3, clusterin, and vitronectin (Table 1). It follows that the increases in ApoB and ApoE found on the human BrMderived HDL would increase its ability to bind to the GAGs on BrM.
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