Bruch's membrane heparan sulfate retains lipoproteins in the early stages of age- related macular degeneration

• 成果类型: Article
• 署名作者: Toomey, Christopher B.; Pflugmacher, Savanna; Park, Kamalu; Pihl, Jessica; Novak, Sammy Weiser; Rodriguez, Jessica; Jalali, Maryam; Jung, Jaesoo; Mozafari, Madeline; Omran, Sima P.; Pormir, Cameron K.; Hauer, Jill; Painter, Chelsea; Walker, Evan; Huang, Alex S.; Boassa, Daniela; Handa, James T.; Aastrup, Teodor; Gordts, Philip L. S. M.; Esko, Jeffrey D.
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; Salk Institute; Johns Hopkins University; Johns Hopkins Medicine; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12681
• DOI: 10.1073/pnas.2500727122
• 发表日期: 2025-06-17
• 关键词: nascent geographic atrophy; basal linear deposit; complement factor-h; retention; localization; drusen; eyes; microperimetry; proteoglycans; expression

摘要

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 micro-balance 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.