The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype.
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.
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Valeriy V
VV
Lyzogubov
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Puran S
PS
Bora
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
Xiaobo
X
Wu
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Leah E
LE
Horn
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; University of Arkansas for Medical Sciences, College of Medicine, Little Rock, Arkansas.
Ryan
R
de Roque
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Xeniya V
XV
Rudolf
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
John P
JP
Atkinson
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. Electronic address: nbora@uams.edu.
Nalini S
NS
Bora
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D057092:Geographic Atrophy / Q000235:genetics* / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D051916:Membrane Cofactor Protein / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout
C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein