Human Molecular Genetics, 2000, Vol. 9, No. 3 353-361
© 2000 Oxford University Press
Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice
Project 8 and 1Reproductive Engineering Section, Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan, 2Pharmaceuticals Research Laboratory 1, Mitsubishi-Tokyo Pharmaceuticals Inc., Yokohama Research Center, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-8502, Japan
The 
4 allele of apolipoprotein E (apoE) is associated with an increased risk of developing Alzheimer’s disease (AD). To accurately determine the isoform-specific effects of human apoE on brain functions under physiological and pathological situations, we created mice expressing human apoE4 isoform in place of mouse apoE by utilizing the gene-targeting technique on the embryonic stem cells (knock-in). The homozygous 4 (4/4) mice correctly expressed human apoE4 in the serum and the brain. The human apoE in the brain was found primarily in the astrocytes as was the mouse apoE in the wild-type (+/+) mice. In the 4/4 mice, the serum cholesterol level was 2.5-fold that of the +/+ littermate controls on a regular diet. This marked elevation was accounted for by an accumulation of very low and low density lipoproteins. In the brains of the 4/4 mice, however, the amounts of total cholesterol and phospholipids were significantly decreased compared with the +/+ littermates. These findings indicate that cholesterol and lipid metabolism is markedly altered in the 4/4 mice. Our human apoE4 knock-in mice will be useful in clarifying the role of apoE in the etiologies of AD and cardiovascular diseases in relation to cholesterol and lipid metabolism.
+ Present address: Laboratory for Neurodegeneration and Signaling, Brain Science Institute, RIKEN (Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
§ To whom correspondence should be addressed. Tel: +81 42 724 6276; Fax: +81 42 724 6314; Email: fujita@ls.m-kagaku.co.jp
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