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Human Molecular Genetics Advance Access published online on June 30, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh199
© 2004 by Oxford University Press
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Article

Independent effects of APOE on cholesterol metabolism and brain A{beta} levels in an Alzheimer disease mouse model

Karen M. Mann 1, Fayanne E. Thorngate 2, Yuko Katoh-Fukui 3, Hiroki Hamanaka 4, David L. Williams 2, Shinobu Fujita 5, Bruce T. Lamb 6*

1 Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA; Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA
2 Department of Pharmacological Sciences, University Medical Center, Stony Brook University, Stony Brook, New York 11794, USA
3 Department of Developmental Biology, National Institute for Basic Biology, Myodaiji-cho, Okazaki 444-8585, Japan
4 Center for Neural Science, New York University, New York, New York 10003-6621, USA
5 Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo, Japan
6 Department of Genetics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106-4955, USA; Center for Human Genetics, University Memory and Aging Center and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA

* To whom correspondence should be addressed. E-mail: btl{at}cwru.edu.


  Abstract

The APOE {varepsilon}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 {varepsilon}4 alleles affects both the age of onset and severity of pathology development. Dosage of APOE {varepsilon}2 and {varepsilon}3 alleles, however, appear to be protective against the effects of {varepsilon}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 A{beta} pathology. However, these models have potential limitations that confound our understanding of the effects of 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 A{beta} metabolism. We have characterized APOE knock-in (KI) 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 A{beta} 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 A{beta} metabolism in a mouse model of Alzheimer's disease.


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