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Bradley D Gelfand, Charles B Wright, Jayakrishna Ambati; Dicer1 deficiency in atrophic and neovascular age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Although Dicer1 is widely reported to be promote angiogenesis in a variety of settings, its contribution to pathological choroidal and retinal angiogenesis is unknown. Insufficiency of Dicer1 is implicated in the pathogenesis of atrophic AMD due to activation of innate immunity. We investigated the ocular pathologies of a mouse model of chronic Dicer1 deficiency, where expression is systemically reduced by 80%, We also tested whether the innate immune adaptor MyD88, also implicated in AMD pathogenesis, contributes to ocular pathologies in this model. Finally, we sought to determine our findings in a library of human AMD specimens.
Dicer1 deficient or age-matched littermate control mice aged 1- to 15-months were examined by fundus photography, fluorescein angiography, histology, and electron microscopy. Dicer1 deficient mice were also bred to MyD88 knockout mice. Statistical association of pathologies with age and genotype was achieved by multiple logistic regression and Chi square test. DICER1 and Alu RNA abundance in human AMD specimens was analyzed by western blotting, q-RT-PCR, in situ hybridization, and immunohistochemistry.
Dicer1 deficient mice exhibited features of dry AMD including basal laminar deposits and focal atrophy of the retinal pigmented epithelium (RPE). Age was strongly associated with incidence of RPE atrophy, first observed in 25% of eyes at 1 mo. and increasing in frequency up to 75% at 10-months (P=0.006). Unexpectedly, Dicer1 deficient mice also demonstrated spontaneous choroidal and retinal neovascularization, characteristic of neovascular AMD. AMD-like pathologies were are accompanied by molecular hallmarks of inflammasome activation. Dicer1 deficient/MyD88 KO mice exhibited significantly reduced RPE atrophy(14% vs. 50%, P<0.01) and choroidal and retinal vascular lesions at 2 mo. of age (5% vs. 50%, P<0.0001). Reduced Dicer1 levels and accumulation of Alu RNA were detected in the RPE, choroid and stroma of human neovascular AMD.
Dicer1 deficiency and innate immune activation may underlie both forms of advanced AMD and Dicer1 deficient mice represent a valuable new model of progressive RPE atrophy and aberrant retinal and choroidal neovascularization. These findings also reveal an unexpected anti-angiogenic role for Dicer1.
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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