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Armin Mohi, Salvatore Grisanti, Martin Rudolf, Translational AMD research; Apolipoprotein mimetic Dual Domain Peptide reduces Neutral Lipid Deposits in murine Bruch's Membrane. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4102.
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© ARVO (1962-2015); The Authors (2016-present)
Massive accumulation of neutral lipids in Bruch’s membrane (BrM) with concomitantly increased hydraulic resistivity and oxidative stress induction is a major age change in the eye and an important pathogenic factor for the development and progression of age-related macular degeneration. Apolipoprotein (Apo) mimetic peptides are highly effective and well tolerated lipid acceptors that might be used to remove these pathogenic deposits. We evaluated the effect of an intravitreally injected dual domain peptide (DDP) containing domain properties of ApoE and ApoA-I in an established mouse model of age-related BrM lipid deposition (ApoEnull).
Four groups (4x; n=6) of 10 month-old ApoEnull mice received a single intravitreal injection of DDP with different dosages (0 µg; 0.6 µg; 1.2 µg; 2.4 µg). The second untreated eye served as an intra-individual control. Thirty days after injection all animals were sacrificed and eyes were enucleated and processed to BrM wholemounts. The specimens were stained with a protocol for BrM specific esterified cholesterol using the fluorescent cholesterol specific dye PFO/D4-GFP (Dettbarn et al. ARVO 2010). The treatment effect on BrM lipid deposition was evaluated semiquantitatively by fluorescence measurements. We calculated for each dose group across all treated vs. untreated eyes the relative difference (%) and tested for significance using the student-t-test.
The vehicle injection (0.9% NaCl, 0 µg DDP) caused no change in BrM esterified cholesterol content (p=0.29). In all other groups we could observe a significant decrease of cholesterol content. The lowest dose showed a significant effect (p<0.001) of 43,5% cholesterol reduction in the treated eyes vs. untreated eyes. The medium and highest DDP dose showed also significant effects (p<0.001) with a cholesterol reduction of 41.7% in the medium dose group and 34.2% with the highest dose.
Our data demonstrated a significant but so far not dose dependant reduction of BrM lipid deposits by DDP with ApoA-I and ApoE domain characteristics. Nevertheless, the treatment effect is lower than with our initially tested ApoA-I mimetic peptides (L-4F, D-4F, ARVO 2011 Rudolf et al. Mohi et al.). A neutral lipid reduction of ca. 70% with a single intravitreal injection of 2.4 µg D-4F shows almost double the treatment effect of the here tested DDP.
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