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Peter Baciu, Jia-Ying Yang, Iona Raymond, Ping Yang, Victoria Treboschi, Glenn J Jaffe; Combined Complement Deregulation and Oxidative Stress in SOD1/CD59a null Mice Develop AMD-like Phenotypes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5008.
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© ARVO (1962-2015); The Authors (2016-present)
Oxidative stress and complement are respective environmental and genetic risk factors highly associated with development of age related macular degeneration (AMD). In vitro studies have identified a synergistic relationship between these two critical components, however, the translatability of these findings in vivo is unknown. To address the in vivo impact we have created a double knockout (DKO) mouse combining the absence of CD59a , reducing complement regulation, with loss of cellular superoxide dismutase 1 ( SOD1), increasing the level of oxidative stress.
Sod1tm1Leb/J null animals were crossed with CD59a (129/Sv x C57 BL/6j) null mice followed by backcrossing progeny through 6 generations onto the Sod1tm1Leb/J parental strain. Genotypes as well as the absence of CRB1 mutation was verified by PCR. Fundus autofluorescence (FAF), color fundus photographic (CF), confocal scanning ophthalmoscopic (cSLO), and optical coherence tomographic(OCT) images were obtained to assess in vivo anatomy, and electroretinograms (ERG) were obtained to measure retinal function in DKO mice and littermate controls.Ocular tissues were analyzed by H&E, immunohistochemistry, and choroidal flat mounts.
Mouse eyes had regions of retinal pigment epithelium (RPE) with hypo- and hyper-pigmentation that increased overtime and was associated with retinal detachment at 6 to 10 months of age. On ERG, scotopic and photopic responses were decreased by 3 months with significant loss by 10 months. At 6 weeks to 3 months of age, 20% of DKO mouse eyes had hypopigmented lesions on CF that had increased reflectance by cSLO and associated hyperautofluorescence by FAF. ICG angiography indicated choroidal non-perfusion within the lesion with occurance of neovascularization resembling retinal angiomatous proliferation ( RAP).
The combined impact of oxidative stress and complement deregulation in DKO mice resulted in the development of ocular phenotypes similar to those seen in AMD including; choroidal abnormalities, RAP lesions, RPE hypo- and hyper pigmentation, retinal detachment, and loss of retinal function.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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