Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 186, Issue 8, Pages 2088-2104Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.03.021
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Funding
- Edward N. and Della L. Thome Memorial Foundation grant
- Lions of Arkansas Foundation, Inc., grant
- Pat and Willard Walker Eye Research Center grant
- Jones Eye Institute (Little Rock, AR) grant
- Protein Production and Purification Core Facility of the Rheumatic Diseases Core Center under Award [P30AR048335]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of General Medical Sciences [R01 GM099111]
- National Institute of Allergy and Infectious Diseases under Award [R01 AI041592]
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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.
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