In AMD, excess lipid accumulation in RPE and BrM is associated with reduced retinal scotopic sensitivity and delayed dark adaptation.15
This lipid deposition also predisposes patients to severe visual loss from choroidal neovascularisation.16
We and others have demonstrated similarities between macrophages and RPE with respect to lipid efflux, or RCT.9, 15–18
There are also studies indicating important roles for ABCA1 and SR-BI in regulating lipid transport19
and amyloid protein metabolism20
in the brain. In the current study, we examine expression of these proteins in the retina and RPE.
In previous studies we demonstrated that HDL and purified ApoA-I can stimulate lipid efflux from the basal surface of RPE cells in culture11
and that cultured human RPE cells express SR-BI.9
We now demonstrate that ABCA1, an ATP binding cassette transporter that is involved in RCT in other tissues, is expressed by cultured human RPE cells. Importantly, we demonstrate that glyburide, an inhibitor of ABCA1 and SR-BI activity,21
inhibited efflux of POS-derived lipids from the basal surface of cultured RPE cells. Thus, RCT in RPE cells in culture is dependent on SR-BI and/or ABCA1 activity. Finally, the present study demonstrates that mouse RPE cells express SR-BI in vivo and that SR-BI+/−
mice show increased BrM thickness, although we did not observe a significant effect on retinal function or dark adaptation as measured using ERG. Significantly, we demonstrate that SR-BI is expressed at the basal surface of the mouse RPE in vivo, where it could participate in RCT.
The results suggest that mouse and human eyes may traffic lipids differently. We have reported that human RPE cells express SR-BI.9
In the mouse SR-BI appears to be expressed exclusively in the RPE (). Tserentsoodol et al
reported expression of SR-BI and SR-BII in both RPE and ganglion cell layers, and ABCA1 in the RPE cell layer in the monkey.22
The observation that SR-BI+/−
mice had abnormal BrM thickness, whereas ABCA1+/−
mice had apparently normal BrM, suggests that, in the mouse, SR-BI function may be more important in maintaining normal BrM structure than ABCA1.
One study of ApoE-deficient mice with excess accumulation of lipid in BrM23
showed abnormalities of retinal scotopic sensitivity and recovery from exposure to photobleach.24
However, studies in which ERG abnormalities were present also reported abnormalities of outer and inner retinal structure. We did not find a similar defect in either scotopic retinal function or dark adaptation, perhaps because microscopic studies of mice with heterozygous mutations in ABCA1 and SR-BI did not show any abnormalities of photoreceptor or inner retinal structure. This distinction suggests that BrM thickening, in the absence of photoreceptor abnormalities, is not sufficient to affect either photoreceptor function or dark adaptation.
Because lipid accumulation in the RPE and Bruch’s membrane is the hallmark of early AMD, understanding the mechanisms of RCT in these tissues may be critical to developing future therapies for this major cause of visual loss.