Summary: New research from UC San Diego suggests that sticky sugar chains called heparan sulfate (HS) within Bruch’s membrane may capture lipoproteins and initiate the formation of drusen, an early hallmark of age-related macular degeneration (AMD). These fat-protein particles, similar to high-density lipoprotein (HDL), accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane, forming deposits that can damage retinal cells and threaten central vision over time.
The study found that eyes affected by AMD have elevated amounts of HS in the macular region of Bruch’s membrane, and that these HS-rich areas correspond to focal clusters of lipoprotein-like particles. Laboratory treatment with modified heparin molecules disrupted this interaction and helped remove bound lipids from AMD tissue, suggesting a possible therapeutic approach that avoids the bleeding risks associated with standard heparin.
Key points:
- HS as a molecular trap: Heparan sulfate in Bruch’s membrane can bind and retain lipoprotein particles, promoting drusen formation.
- Clinical association: AMD-affected maculas show greater HS accumulation and co-localized lipoprotein clusters compared with non-AMD tissues.
- Therapeutic potential: Modified, non-anticoagulant heparin-like compounds can disrupt HS–lipoprotein binding and may help clear harmful lipids from Bruch’s membrane without causing bleeding.
Source: UC San Diego
Understanding AMD and drusen formation
Age-related macular degeneration (AMD) is a leading cause of vision loss among older adults. Early AMD is characterized by drusen—small to large deposits composed primarily of lipids, proteins and waste products—that build up between the RPE and Bruch’s membrane at the back of the eye. While drusen are commonly used as a clinical marker for AMD progression, they are also active contributors to retinal dysfunction. Their presence can disrupt the exchange of nutrients and waste between the retina and the choroid, triggering inflammation and progressive damage to photoreceptors and RPE cells.
Researchers long suspected lipoproteins—particle complexes that carry lipids through tissues—play a central role in drusen biogenesis. What remained unclear was the molecular mechanism that causes these lipoproteins to become immobilized within Bruch’s membrane. The new findings identify heparan sulfate as a likely binding partner that physically traps lipoprotein-like particles, helping to seed and expand drusen deposits in the macula.
This research, published in Proceedings of the National Academy of Sciences (PNAS) and led by Christopher B. Toomey, M.D., Ph.D., at UC San Diego’s Shiley Eye Institute, examined human donor tissue and demonstrated a clear spatial relationship between HS density and lipoprotein clustering. Biochemical experiments showed that intact HS is required for robust lipoprotein binding to Bruch’s membrane; when HS was removed or masked, lipoprotein attachment diminished substantially.
Implications for treatment and future research
One promising outcome is the ability to displace bound lipids from AMD tissue using heparin-like molecules. The investigators treated AMD specimens with heparin, which competes with HS for lipoprotein binding, and observed effective washout of the trapped particles. Importantly, the study highlights non-anticoagulant or specially modified heparins that can interfere with HS–lipoprotein interactions without carrying the bleeding risk of conventional heparin therapy.
Translating this discovery into a therapeutic strategy will require further study. Key next steps include testing safety and efficacy of modified heparin compounds in preclinical models, optimizing delivery to the macula, and determining whether early intervention can prevent drusen accumulation or even reduce existing deposits to preserve vision. The study underscores the value of targeting the extracellular matrix—specifically HS in Bruch’s membrane—as a novel approach for treating early AMD.
About this AMD research news
Author: Lizelda Lopez
Source: UC San Diego
Contact: Lizelda Lopez, UCSD
Image: Image credit: Neuroscience News
Original research: Findings published in Proceedings of the National Academy of Sciences (PNAS)