Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration
Year: 2025
Type: article
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.
Authors: Christopher B. Toomey, Savanna Pflugmacher, Kamalu Park, Jessica Pihl, Sammy Weiser Novak, Jessica Rodriguez, Maryam Jalali, Jaesoo Jung, Madeline Mozafari, Sima P. Omran, Cameron K. Pormir, Jill Hauer, Chelsea Painter, Evan Walker, Alex S. Huang, Daniela Boassa, James T. Handa, Teodor Aastrup, Philip L. S. M. Gordts, Jeffrey D. Esko
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Foundation Fighting Blindness, Larry L. Hillblom Foundation, International Retinal Research Foundation, Research to Prevent Blindness, Novartis, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Alcon Research Institute
Awards: G1185693225, G1235137611, G1271092380, G1675750721, G2138053155, G2743576339, G2818328167, G2859307317, G3004359925, G3395350662, G3590001840, G4172656364, G4580167800, G5129523443, G5502030292, G5545623075, G5674560722, G7390778054, G817487125, The Heparan Sulfate Landscape in Complement Regulation, Bruch's Membrane-On-A-Chip to Study Drusen Formation in AMD, Dynamic Variable Aqueous Humor Outflow and Glaucoma Therapies in the Human Eye, Does age/stress-induced mitochondrial dysfunction induce variations in RPE phenotype in AMD?
OpenAlex ID: W4411272834