Altered cholesterol metabolism in human apolipoprotein E4 knock-in mice

The epsilon 4 allele of apolipoprotein E (apoE) is associated with an incre ased risk of developing Alzheimer's disease (AD), To accurately determine t he isoform-specific effects of human apoE on brain functions under physiolo gical and pathological situations, we created mice expressing human apoE4 i soform in place of mouse apoE by utilizing the gene-targeting technique on the embryonic stem cells (knock-in), The homozygous epsilon 4 (4/4) mice co rrectly 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 t he 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 th e +/+ littermates. These findings indicate that cholesterol and lipid metab olism is markedly altered in the 4/4 mice. Our human apoE4 knock-in mice wi ll be useful in clarifying the role of apoE in the etiologies of AD and car diovascular diseases in relation to cholesterol and lipid metabolism.