Abstract
Abstract: :
Purpose: Apolipoprotein E (apoE) isoform expression has been linked to neurodegenerative changes observed in the brains of aged individuals succumbing to Alzheimer's disease. These studies were designed to determine the relative roles of apoE isoform expression and aging on the integrity of the retina and RPE/chorioid in a potential mouse model of age-related macular degeneration (AMD). Methods: Three human apoE targeted replacement (TR) mouse lines, each expressing one of the three common human apoE isoforms (apoE2, E3 or E4) 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 fed a diet of normal mouse chow. Blood was collected from aged apoE TR mice (mean age 107 wk) and age-matched, wild-type controls (mean age 96 wk), and serum cholesterol levels were measured. Mice were then euthanized, and the eyes were dissected, fixed in a mixed aldehyde solution, embedded in paraffin or Epon and processed for light and 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 of hemotoxylin and eosin-stained sections, no gross morphological alterations were observed in the retina or RPE/choroid, as compared to wild-type eyes. In particular, no distinct RPE basal laminar deposits were observed, nor was there a detectable thickening of Bruch's membrane. These observations were confirmed ultrastructurally. Conclusion: 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 apoE isoform expression alone does not result in detectable degeneration of the retina or RPE/choroid, even in aged mice. Therefore we are currently developing a population of aged apoE TR mice maintained on a high cholesterol, high saturated fat diet.
Keywords: 308 age-related macular degeneration • 316 animal model • 561 retinal degenerations: cell biology