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G. Malek, P.M. Sullivan, B.E. Mace, D. Schmechel, C. Bowes Rickman; Effect of Diet and Targeted Replacement Human APOE Isoforms in Aged Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1737.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Age related macular degeneration (AMD) is a multifactorial disorder affecting older adults in which genetic factors are likely to play a role. Previously, the apolipoprotein E (APOE) gene has been implicated in AMD. APOE-ε4 allele is associated with a protective effect, while the ε2 allele may increase disease risk. These studies were designed to determine the relative roles of APOE isoform expression and diet on the integrity of the retina and RPE/choroid in a potential mouse model of macular degeneration. Methods: Three human APOE targeted replacement (TR) mouse lines, each expressing one of the three common human APOE isoforms (ε2, ε3, ε4) were created by replacing only the coding sequences of mouse APOE with human APOE allele-specific coding sequences, without disturbing any known regulatory sequences. Mice were bred and housed conventionally, and were fed a high fat American or sodium cholate diet. Mice on normal chow served as controls. Blood was collected from the aged APOE TR mice on each diet, and serum cholesterol levels were measured. Mice were euthanized, and the eyes were dissected. The right eyes were fixed in 4% paraformaldehyde, cryoprotected and processed for light microscopy, while the left eyes were fixed in 2% gluteraldehyde, embedded in Spurrs resin and processed for electron microscopy. Results: APOE TR mice express APOE isoforms at physiological levels and in temporal and spatial patterns similar to wild-type mice and humans. Upon histological analysis, in comparison to mice on the normal diet, mice on the high fat American diet demonstrated a number of RPE changes including atrophy and vacuolization. Mice on the cholate diet also demonstrated RPE changes as well as an increase in RPE basal infoldings. Finally, sub retinal and sub RPE deposits were detected in some eyes. Conclusions: Epidemiological studies have suggested a constellation of risk factors contribute to the pathogenesis of neurodegenerative disease, possibly including AMD. These include specificity of APOE isoform expression, ageing and diet. Our findings demonstrate that specific isoform expression alone in aged animals results in only mild degenerative changes of the RPE. APOE isoform expression combined with a high fat American diet results in marked changes in the RPE. More severe RPE changes reminiscent of changes seen in AMD developed in animals on the sodium cholate diet, possibly due to sodium cholates’ ability to enhance cholesterol absorption and/or induce inflammation.
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