A lasered human amelotin transgenic mouse model displays progressive outer retinal pathology and hydroxyapatite deposition similar to geographic atrophy

Authors

• D Rajapakse Todd
• J Fan
• D Daily
• L Dong
• K Peterson
• R Fariss
• G Wistow

Abstract

Geographic atrophy (GA) is a common form of age-related macular degeneration and is characterized by death of photoreceptors, which precedes the loss of retinal pigment epithelial (RPE) cells. Vision loss due to GA has no effective treatment, reflecting the complexity of the disease and lack of suitable animal models. Early signs of GA are “soft” drusen, extracellular accumulations of lipids, proteins, and mineralized calcium phosphate, hydroxyapatite (HAP), along Bruch' membrane. We discovered that amelotin (AMTN) an extracellular protein involved in formation of dental enamel, is induced in RPE in GA and is associated with HAP mineralization of drusen. Healthy RPE does not express AMTN. We have created a transgenic (Tg) mouse model in which constitutive expression of human AMTN is targeted to RPE using a construct based on the mouse gene for RPE65, a cell-specific protein. Human AMTN is expressed specifically in RPE and, by itself creates some abnormalities relevant to AMD pathology. To induce a calcium flux, retinas of Tg mice were lasered at adjacent sites using a slit lamp system with an OcuLight GLx ophthalmic laser 100µm spots, 0.1 sec duration at ±120 mW of power. This injury resulted in deposits containing HAP, reminiscent of GA drusen, 2-weeks post-laser. While wild type littermates had normal wound repair, fluorescent imaging and optical coherence tomography showed progressive obliteration of photoreceptors within lesions, but an unaffected inner retina. We further observed microglial recruitment and functional retinal deficits. We propose this mouse model as an attractive tool for GA studies and drug-discovery.

Scientific Focus Area: Cell Biology

This page was last updated on Monday, September 25, 2023