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M. d. Cano, N. Fijalkowski, N. Kondo, K. Clifford, J. T. Handa; Advanced Glycation Endproducts (AGEs) Favor LDL Retention in the Fundus. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6162.
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Lipoprotein accumulation in the fundus has been implicated in Age-related Macular Degeneration (AMD), which could alter the function of the RPE and Bruch membrane. Importantly, lipoproteins if retained and modified, are potent stimulators of complement mediated inflammation. Lipoproteins normally diffuse across Bruch membrane, but aging changes to the matrix provide optimal conditions for lipoprotein retention. This study was conducted to evaluate if AGE formation promotes LDL retention in Bruch membrane.
: 5 month C57BL6 mice were treated for 8 weeks with subcutaneous injections of D-Galactose (50 mg/kg), PBS or Dgal and Nphenacylthiazolium bromide PTB (10mg/kg), which cleaves AGE crosslinks. After treatment, mice were injected IV with low density lipoprotein (LDL; 5 µg/µL, 500 µg total) labeled with Rhodamine. Mice were sacrificed 5 minutes, 24 and 72 hours after LDL injection. Eyes were fixed and cryopreserved. The location of LDL in the fundus was assessed by confocal microscopy. Fluorescence intensity was quantified using Zeiss’s Axiovision software.
LDLs were retained in the RPE of the Dgal mice 24h after injection, with 629.30±42.66 compared to 124±43.20 and 133±177.31 relative fluorescence units in the PTB D-gal and the PBS controls, p= 0.02 and P= 0.04, respectively. LDLs were also retained 72h after injection in the Dgal group 223.60±115.53, relative to PBS controls (no fluorescence; p= 0.03). LDLs were increased in Bruch membrane of Dgal mice at 24h and 72h after injection compared to the PTB Dgal and PBS controls. At 24h, the relative fluorescence was 1806.02±575 in the Dgal group compared to 507 ± 62 and 36.87 ± 32 in the PTB Dgal and PBS controls (p= 0.01 and 0.006), respectively. After 72h, the relative fluorescence was 5072 ± 3341 in Dgal mice compared to 466.66±109 and 325±456 in the PTB Dgal and PBS groups (p= 0.04 and p= 0.04), respectively.
AGE formation favors the retention of LDLs in the RPE and Bruch Membrane. Given the high oxidative stress environment, these findings suggest that lipoprotein retention would favor the formation of oxidized lipoproteins, which are potent activators of complement.
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