Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration
Abstract
Lipoprotein retention in Bruch’s membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch’s membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch’s membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Christopher B. Toomey
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Savanna Pflugmacher
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Kamalu Park
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Jessica Pihl
Glycobiology Research and Training Center, University of California San Diego
Sammy Weiser Novak
Waitt Advanced Biophotonic Core, Salk Institute
Jessica Rodriguez
Glycobiology Research and Training Center, University of California San Diego
Maryam Jalali
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Jaesoo Jung
Glycobiology Research and Training Center, University of California San Diego
Madeline Mozafari
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Sima P. Omran
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Cameron K. Pormir
Department of Cellular and Molecular Medicine, University of California San Diego
Jill Hauer
Glycobiology Research and Training Center, University of California San Diego
Chelsea Painter
Glycobiology Research and Training Center, University of California San Diego
Evan Walker
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Alex S. Huang
Viterbi Family Department of Ophthalmology and Shiley Eye Institute, University of California San Diego
Daniela Boassa
Waitt Advanced Biophotonic Core, Salk Institute
James T. Handa
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins Medical Institute
Teodor Aastrup
Attana AB, Stockholm
Philip L. S. M. Gordts
Glycobiology Research and Training Center, University of California San Diego
Jeffrey D. Esko