Abstract
Purpose: :
An SOD1 (-/-) mouse model of macular degeneration has been recently described by Imamura et al, PNAS 2006: 103, 11282-7. The purpose of this study was to validate the macular degeneration findings in the SOD1 (-/-) mouse model of ARMD.
Methods: :
We analyzed the funduscopic appearance of SOD1 (-/-) and SOD1 (+/-) mice ranging from 3 - 15 months of age in a longitudinal study using indirect ophthalmoscopy and light and electron microscopy. Mice used in this study were created by gene targeting, using a vector that resulted in the deletion of a 1.8 kb RsaI-HindIII fragment from exons 3-4 in the SOD1 gene. The CD1-Sod1[tm1Cje] mouse does not express SOD1 as determined by Western blotting and enzyme assays. The mice were maintained under normal laboratory conditions with light exposure of 12 hours on and 12 hours off.
Results: :
We found very few, if any, drusen-like abnormalities until the SOD1 (-/-) mice were 8 months of age. This was followed by a progressive age-related increase in yellow punctate drusen-like changes. It wasn’t until the mice were 12 - 15 months of age when the number of outer retinal abnormalities were remarkable, approaching several hundreds of spots per retina. Diffuse areas of granularity and irregularity of the RPE were also present by 12 - 15 months. Surprisingly, initial histologic examination of 12 month old mice did not reveal typical drusen. However, electron microscopy revealed a broad pattern of dense deposits, resembling basal laminal deposits, at the basal surface of the RPE. Multilayered choroidal endothelial cell basement membranes were frequently observed. Histologic examination of 15 month old retinas showed an increase in dense deposits at the level of the RPE and Bruch’s membrane. Pigmented RPE cells were seen having migrated around degenerating outer segments of photoreceptors.
Conclusions: :
Our initial characterization of the SOD1 (-/-) mouse (CD1-Sod1[tm1Cje]) shows a variety of interesting fundus findings with several significant differences from the phenotype described by Imamura et al. Electron microscopy findings are indicative of outer retina/RPE abnormalities and photoreceptor degeneration. Additional histology studies with more mice is in progress.
Keywords: age-related macular degeneration • transgenics/knock-outs • oxidation/oxidative or free radical damage