1. ApoA-I Mimetic Peptide 4F Reduces Age-Related Lipid Deposition in Murine Bruch’s Membrane and Causes Its Structural Remodeling.
- Author
-
Rudolf, Martin, Mir Mohi Sefat, Armin, Miura, Yoko, Tura, Aysegül, Raasch, Walter, Ranjbar, Mahdy, Grisanti, Salvatore, Aherrahrou, Zouhair, Wagner, Anna, Messinger, Jeffrey D, Garber, David W, Anantharamaiah, GM, and Curcio, Christine A
- Subjects
- *
RETINAL degeneration , *TRANSMISSION electron microscopy , *VASCULAR endothelial growth factors , *BILAYER lipid membranes , *CELL membranes - 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 ApoEnullmice ≥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. [ABSTRACT FROM PUBLISHER]
- Published
- 2018
- Full Text
- View/download PDF