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

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 À/À 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 À/À mice that are consistent with human dry AMD. These findings provide the exciting possibility of using Cd46 À/À 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 À/À mouse model of dry AMD a unique advantage over other mouse models using knockout strains. Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in individuals >50 years of age in the United States and around the world. 1e5 This disease causes a progressive destruction of the macula, leading to the loss of central vision. AMD is a chronic degenerative process with multiple risk factors. 2,3,6e17 Nearly two million individuals in the United States alone are currently afflicted with AMD. This number is expected to grow in part because of increasing life expectancy. 5 Clinically, AMD is usually classified into two formsdnonexudative (dry type) and exudative (wet type). Although the dry form of AMD is more prevalent (approximately 85% of the cases) and a precursor to wet AMD, the fundamental processes underlying dry AMD are particularly not well understood. 2e4,6e10 Several agents to treat dry AMD are currently in the developmental stage. However, no effective treatment option is currently available. 11,12 Novel therapeutic targets for dry AMD need to be discovered.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…C3ar1 tm1Cge mutants show very slow PR degeneration with about 20% loss at 14 months [423]. Cd46 tm1Atk show different rates of PR nuclei loss in male and female mice with 23% and 31% at 12 months of age, respectively [424]. Mutations in Cx3cr1, normally expressed in immune cells including microglia, were associated with PR cell loss.…”

Complement Dysregulation and Disease: Insights from Contemporary Genetics

“…However, human genetic studies have not identified an association between CD46 mutations and AMD. Furthermore, a spontaneously occurring mouse model of AMD has been described (94–96). This genetic model demonstrates a multifocal, bilateral spontaneous choroidal neovascularization, which leads to early, persistent neovascular lesions that result in death.…”

Complement family member CFI polymorphisms and AMD susceptibility from a comprehensive analysis

“…Increasing evidence has shown that inflammatory processes, especially the complement activation pathway, may play a major role in the pathogenesis of AMD [48,49]. Thus, we can regulate complement and inflammatory system to delay the development of dry AMD [50,51]. Next, to identify some novel detection markers and target drugs for different types of AMD is the current and future research focus on the direction.…”