Abstract
Purpose: :
Age-Related Macular Degeneration (AMD) is characterized by the accumulation of lipid- and protein-rich deposits in Bruch’s Membrane (BrM). A consequent decrease in hydraulic conductivity and impairment of transport through BrM is considered to play a central role in the pathogenesis of AMD. The mechanism of deposit formation however is not well understood. In other diseases like atherosclerosis, the interaction of ApoB100 and the extracellular matrix proteoglycan Biglycan was shown to be a key step in lipid entrapment. The aim of this study was to test the effect of the simultaneous overexpression of human ApoB100 and biglycan genes in combination with a high-cholesterol diet on BrM morphology in transgenic mice.
Methods: :
6-week-old homozygous ApoB100 (apoB+/+), Biglycan (biglycan+/+), hemizygous double transgenic (apoB+/- x biglycan+/-) and C57bl/6 female mice were fed either a standard chow or a diet supplemented with 2% cholesterol for 17 weeks. Animals were sacrificed, serum lipid levels were measured and eyes were processed for Transmission Electron Microscopy according to standard protocol. Morphometric analysis of digitally acquired TEM images of BrM was performed using Adobe PhotoShop with the FoveaPro plug-in and the ImageJ analysis package.
Results: :
Double transgenic animals fed a high-cholesterol diet showed a statistically significant (p<0.05) increase in BrM thickness as well as basal deposits of a morphology compatible with basal linear deposists (BlinD). This correlated well with elevated total and LDL cholesterol levels. Biglycan transgenic animals showed a marked but diet-independent increase in BrM thickness with clear differences in BrM morphology.
Conclusions: :
Our results indicate that ApoB100/biglycan interaction may indeed play a role in the pathogenesis of AMD. Biglycan may also contribute to BrM changes via pathways unrelated to lipid metabolism.
Keywords: age-related macular degeneration • lipids • proteoglycans/glycosaminoglycans