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Michael Landowski, Jindong Ding, Mikael Klingeborn, Una Kelly, Marybeth Groelle, Catherine Bowes Rickman; Effect of Complement Factor H Variants in Regulating AMD-like Pathologies In Vivo.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6526.
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© ARVO (1962-2015); The Authors (2016-present)
The Y402H polymorphism in the complement factor H (CFH gene, FH protein) is associated with increased risk for age-related macular degeneration (AMD), but the role of the risk-associated H402 variant in AMD remains unclear. We generated transgenic mouse lines expressing the same concentration of full-length human normal Y402 or risk-associated H402 variants of the FH protein on a mouse Cfh knockout background (CFH-Y:Cfh-/- and CFH-HH:Cfh-/-, respectively) to mechanistically study the function of FH variants in AMD pathogenesis in vivo. We tested the hypotheses (1) that an AMD-like phenotype will develop in old CFH:Cfh-/- mice following 8 weeks on a high fat, cholesterol-enriched (HFC) diet and (2) that there is a variant-associated difference in the amount of sub-RPE deposit, visual loss, and RPE damage between these lines.
90 week-old male C57BL/6J, CFH-Y:Cfh-/-, CFH-HH:Cfh-/- and Cfh-/- mice were housed conventionally, under ambient conditions and maintained on water ad libitum and fed either a normal mouse chow diet (ND) or switched to a HFC diet for 8 wks. ERGs and plasma samples were obtained prior to termination. Eyes were collected and processed for electron microscopy for quantification of sub-RPE deposit load, immunofluorescence to assess RPE damage and routine histology.
Old mice expressing only human FH that were fed a HFC diet developed vision loss, larger sub-RPE deposits, and more multinucleated RPE cells compared to their age-matched, normal diet controls. As we have previously shown, aged Cfh-/- mice did not develop an AMD-like phenotype following HFC diet. The phenotype in CFH-Y:Cfh-/- mice fed a HFC diet appears to be less severe than in the CFH-HH:Cfh-/- mice fed a HFC diet.
CFH-Y:Cfh-/- and CFH-HH:Cfh-/- mice on HFC diet develop an AMD-like phenotype. The less severe AMD-like phenotype observed in aged CFH-Y:Cfh-/- mice on HFC diet compared to aged CFH-HH:Cfh-/- mice on HFC diet suggests that the Y402 variant is protective against AMD-like pathology. These models will be useful in elucidating the molecular mechanisms underlying the association of the H402 variant with AMD risk.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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