The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration–Like Phenotype

Valeriy V. Lyzogubov, Puran S. Bora, Xiaobo Wu, Leah E. Horn, Ryan de Roque, Xeniya V. Rudolf, John P. Atkinson, Nalini S. Bora

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46−/− mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice: accumulation of autofluorescent material in and hypertrophy of the RPE, dense deposits in and thickening of Bruch's membrane, loss of photoreceptors, cells in subretinal space, and a reduction of choroidal vessels. Collectively, our results demonstrate spontaneous age-related degenerative changes in the retina, RPE, and choroid of Cd46−/− mice that are consistent with human dry AMD. These findings provide the exciting possibility of using Cd46−/− mice as a convenient and reliable animal model for dry AMD. Having such a relatively straight-forward model for dry AMD should provide valuable insights into pathogenesis and a test model system for novel drug targets. More important, tissue-specific expression of CD46 gives the Cd46−/− mouse model of dry AMD a unique advantage over other mouse models using knockout strains.

Original languageEnglish
Pages (from-to)2088-2104
Number of pages17
JournalAmerican Journal of Pathology
Volume186
Issue number8
DOIs
StatePublished - Aug 1 2016

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