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(Investigative Ophthalmology and Visual Science. 2001;42:1891-1900.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Effects of Cholesterol and Apolipoprotein E on Retinal Abnormalities in ApoE-Deficient Mice

John M. Ong1, Nadia C. Zorapapel1, Kathryn A. Rich2, Ryan E. Wagstaff3, Robert W. Lambert3, Shari E. Rosenberg1, Fahimeh Moghaddas1, Ashkan Pirouzmanesh1, Annette M. Aoki1 and M. Cristina Kenney1

1 From the Molecular Eye Research Laboratory, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; 2 Huntington Medical Research Institutes, Pasadena, California; and 3 ISTA Pharmaceuticals, Inc., Irvine, California.

PURPOSE. To examine the pathologic changes in the retina of apolipoprotein E (apoE)-deficient mice fed a high-cholesterol diet.

METHODS. ApoE-deficient mice (ApoE) were maintained on either regular mouse chow (ApoE-R) or a high-cholesterol diet (ApoE-C) for 25 weeks. Age-matched control C57BL/6J mice (C57) were also maintained on either regular mouse chow (C57-R) or a cholesterol-containing diet (C57-C). Retinal function was assessed by dark-adapted electroretinography (ERG). The eyes were embedded, sectioned, and analyzed by histologic and immunohistochemical methods, as well as by light and transmission electron microscopy.

RESULTS. After the 25-week feeding period, ERG tracings of ApoE-C mice revealed significant increases of a- and b-wave implicit times when compared with the C57-R group of mice. In addition, there were reductions in oscillatory potential (OP) amplitudes in the ApoE-C group. However, a- and b-wave amplitudes appeared to be unchanged among the four groups of mice. Light microscopic examination of the retinas showed that compared with control C57-R mice, ApoE-C mice had significantly lower cell numbers in the inner and outer nuclear layers (85.1% ± 4.6%, P < 0.05 and 81.4% ± 3.7%, P < 0.01 of C57-R controls, respectively). Transmission electron microscopy of apoE-deficient mice revealed cells of the inner nuclear layer with condensation of nuclear chromatin and perinuclear vacuolization in focal areas. Bruch’s membrane was also found to be thicker, and its elastic lamina appeared disorganized and discontinuous. Immunohistochemistry demonstrated diminished or no immunoreactivity for carbonic anhydrase II and calretinin in the retinal layers of apoE-deficient mice.

CONCLUSIONS. Overall, there were increasing abnormalities of retinal function and cellular morphology among the four groups of mice in the order of C57-R < C57-C < ApoE-R < ApoE-C. These findings suggest that apoE and/or cholesterol play an important role in retinal function.




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