Human Molecular Genetics Advance Access originally published online on June 30, 2004
Human Molecular Genetics 2004 13(17):1959-1968; doi:10.1093/hmg/ddh199
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Human Molecular Genetics, Vol. 13, No. 17 © Oxford University Press 2004; all rights reserved
Independent effects of APOE on cholesterol metabolism and brain Aß levels in an Alzheimer disease mouse model
1Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA, 2Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, OH 44106, USA, 3Department of Pharmacological Sciences, University Medical Center, Stony Brook University, Stony Brook, NY 11794, USA, 4Department of Developmental Biology, National Institute for Basic Biology, Myodaiji-cho, Okazaki 444-8585, Japan, 5Center for Neural Science, New York University, New York, NY 10003-6621, USA and 6Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo, Japan
Received March 30, 2004; Accepted June 15, 2004
The APOE 
4 allele is the most significant genetic risk factor associated with Alzheimer's disease to date. Epidemiological studies have demonstrated that inheritance of one or more 4 alleles affects both the age of onset and the severity of pathology development. Dosage of APOE 2 and 3 alleles, however, appear to be protective against the effects of 4. Although much of the biology of APOE in peripheral cholesterol metabolism is understood, its role in brain cholesterol metabolism and its impact on AD development is less defined. Several APOE transgenic models have been generated to study the effects of APOE alleles on APP processing and Aß pathology. However, these models have potential limitations that confound our understanding of the effects of apolipoprotein E (APOE) levels and cholesterol metabolism on disease development. To circumvent these limitations, we have taken a genomic-based approach to better understand the relationship between APOE alleles, cholesterol and Aß metabolism. We have characterized APOE knock-in mice, which express each human allele under the endogenous regulatory elements, on a defined C57BL6/J background. These mice have significantly different serum cholesterol levels and steady-state brain APOE levels, and yet have equivalent brain cholesterol levels. However, the presence of human APOE significantly increases brain Aß levels in a genomic-based model of AD, irrespective of genotype. These data indicate an independent role for APOE in cholesterol metabolism in the periphery relative to the CNS, and that the altered levels of cholesterol and APOE in these mice are insufficient to influence Aß metabolism in a mouse model of Alzheimer's disease.
* To whom correspondence should be addressed at: Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA. Tel: +1 2163682979; Fax: +1 2163683432; Email: btl{at}cwru.edu