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M. Rudolf, M. E. Clark, J. D. Messinger, S. Grisanti, D. W. Garber, C. A. Curcio; ApoA-I Mimetic Peptide Reduces Lipid Deposition in Murine Bruch’s Membrane After Intravitreal Injection. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2984.
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The age-related accumulation of neutral lipids in Bruch’s membrane (BrM) with concomitantly increased hydraulic resistivity is a major age change of importance to the pathogenesis of age-related macular degeneration (ARMD). ApoA-I mimetic peptides are a new class of small, highly effective lipid acceptors with a high anti-inflammatory potential. In a mouse model of age-related BrM lipid deposition we evaluated the effect of the intravitreally injected peptide L-4F on BrM integrity and structure.
In 3 groups of seven 8 month-old ApoEnull mice we tested 3 doses of L-4F (A 0.6 µg; B 1.2 µg; C 2.4 µg). One eye per mouse received a single injection of L-4F. The second untreated eye served as a within-individual control. Thirty days after injection mice were sacrificed, and the eyes were enucleated and processed for transmission electron microscopy. The treatment effect on BrM integrity was evaluated by determining the ratio of translucent vesicles (presumed lipids) to dense BrM structure (value of 1= full integrity) using stereological methods. F-Test was performed for statistical analysis.
Control eyes across all groups routinely exhibited BrM translucent vesicles resulting in reduced BrM integrity (0.61 ± 0.11). In each group treated eyes demonstrated a significant improvement of BrM integrity. This effect was detectable even in the lowest dose group (A , 0.76 ± 0.07; p=0.002) but BrM in that group was still thickened and irregular. In comparison, group B (0.89 ± 0.05; p=0.003) and C (0.78 ± 0.07; p=0.04) showed improved BrM integrity, a more uniform BrM structure, and reduced BrM thickness.
Our data demonstrated an L-4F-induced reduction of BrM lipids with a concomitant structural remodeling of BrM. The overall treatment effect on BrM integrity, structure, and thickness was more pronounced in groups B and C, which received higher L-4F doses. ApoA-I mimetic peptides are a potential tool for the prevention/treatment of dry ARMD by treating effectively ARMD-relevant pathogenic lipid deposition in BrM. Future work will determine if this effect occurs through lipid removal, reducing inflammation, or both.
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