Age-related macular degeneration (AMD) is the leading cause of irreversible central blindness in elderly populations of industrialized nations.
One of the strongest susceptibility genes for AMD is complement factor H (CFH); however, its impact on AMD pathobiology remains unresolved. As reported in the recently published paper in Proceedings of the National Academy of Sciences (PNAS), a new model of AMD has been identified.
Here, the effect of the principal AMD-risk–associated CFH variant (Y402H) on the development and progression of age-dependent AMD-like pathologies was determined in vivo. Transgenic mice expressing the full-length normal human CFH Y402 (CFH-Y/0) or the AMD-risk associated CFH H402 (CFH-H/H) variant on a Cfh knock-out background were aged to 90 weeks and switched from normal diet to a high fat, cholesterol-enriched (Western) diet for 8 weeks. The resulting phenotype was compared with age-matched controls maintained on a normal diet.
Remarkably, an AMD-like phenotype consisting of vision loss, increased retinal pigmented epithelium (RPE) stress, and increased sub-RPE deposits was detected only in aged CFH-H/H mice following the Western diet. These changes were not observed in aged CFH-Y/0 mice or in younger (36- to 40-week-old) CFH mice of both genotypes fed either diet. Biochemical analyses of aged CFH mice after the Western diet revealed genotype-dependent changes in plasma and eyecup lipoproteins, but not complement activation, which correlated with the AMD-like symptoms in old CFH-H/H mice. Specifically, apolipoproteins B48 and A1 are elevated in the RPE/choroid of the aged CFH-H/H mice compared with age-matched control CFH-Y/0 fed a Western diet. Hence, we demonstrate a functional consequence of the Y402H polymorphism in vivo, which promotes AMD-like symptoms and affects lipoprotein levels in aged mice.
“These findings help explain why complement based therapies have failed to improve AMD and support targeting lipoproteins as a viable therapeutic strategy for treating AMD,” said Catherine Bowes Rickman, PhD professor of ophthalmology and corresponding author.