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ABSTRACT
Purpose: Accumulation of lipoprotein-derived lipids including esterified and unesterified cholesterol in Bruch’s membrane of human eyes is a major age-related change involved in initiating and sustaining soft drusen in age-related macular degeneration (AMD). The apolipoprotein (apo) A-I mimetic peptide 4F is a small anti-inflammatory and anti-atherogenic agent, and potent modifier of plasma membranes. We evaluated the effect of intravitreally-injected 4F on murine Bruch’s membrane.
Methods: We tested single intravitreal injections of 4F doses (0.6 µg, 1.2 µg, 2.4 µg, and placebo scrambled peptide) in ApoEnull mice ≥10 months of age. After 30 days, mice were euthanized. Eyes were processed for either direct immunofluorescence detection of esterified cholesterol (EC) in Bruch’s membrane whole mounts via a perfringolysin O-based marker linked to green fluorescent protein or by transmission electron microscopic visualization of Bruch’s membrane integrity. Fluorescein isothiocyanate-conjugated 4F was traced after injection.
Results: All injected eyes showed a dose-dependent reduction of Bruch’s membrane EC with a concomitant ultrastructural improvement compared to placebo treated eyes. At a 2.4 µg dose of 4F, EC was reduced on average by ~60% and Bruch’s membrane returned to a regular pentalaminar structure and thickness. Tracer studies confirmed that injected 4F reached intraocular targets.
Conclusion: We demonstrated a highly effective pharmacological reduction of EC and restoration of Bruch’s membrane ultrastructure. The apoA-I mimetic peptide 4F is a novel way to treat a critical AMD disease process and thus represents a new candidate for treating the underlying cause of AMD.
Acknowledgment
We thank Christine Örün for technical assistance.
Declaration of interest
Author MR holds intellectual property (code P) related to this manuscript. Authors MR and CAC hold commercial interest (code C) related to this manuscript. All other authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
Funding
This project was partly supported the International Retinal Research Foundation (IRRF) USA, the Euretina Innovation Award 2011, the AMD-Förderpreis der Deutschen Ophthalmologischen Gesellschaft 2009, by NIH grants P01-34343, R01 EY06109, Macula Vision Research Foundation and unrestricted funds from Research to Prevent Blindness and from the EyeSight Foundation of Alabama to the Department of Ophthalmology at UAB.