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Journal of Lipid Research, Vol. 48, 1022-1034, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of ß-amyloid precursor protein

Gavin H. Tansley^1,*, Braydon L. Burgess^1,*, Matt T. Bryan, Yuan Su, Veronica Hirsch-Reinshagen^*, Jonathan Pearce^*, Jeniffer Y. Chan^*, Anna Wilkinson^*, Jeanette Evans^*, Kathryn E. Naus^*, Sean McIsaac^*, Kelley Bromley, Weihong Song, Hsui-Chiung Yang, Nan Wang^**, Ronald B. DeMattos and Cheryl L. Wellington^2,*

^* Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Lilly Research Laboratories, Indianapolis, IN
Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
^** Department of Medicine, Columbia University, New York, NY

Published, JLR Papers in Press, February 10, 2007.

¹ G. H. Tansley and B. L. Burgess contributed equally to this work.

² To whom correspondence should be addressed. e-mail: cheryl{at}cmmt.ubc.ca

Although intracellular cholesterol levels are known to influence the proteolysis of ß-amyloid precursor protein (APP), the effect of specific genes that regulate cholesterol metabolism on APP processing remains poorly understood. The cholesterol transporter ABCG1 facilitates cholesterol efflux to HDL and is expressed in brain. Notably, the human ABCG1 gene maps to chromosome 21q22.3, and individuals with Down syndrome (DS) typically manifest with Alzheimer's disease (AD) neuropathology in their 30s. Here, we demonstrate that expression of ABCG1 enhances amyloid-ß protein (Aß) production in transfected HEK cells in a manner that requires functional cholesterol transporter activity. ABCG1-expressing cells also exhibit increased secreted APP (sAPP) and sAPPß secretion and display increased cell surface-associated APP. These results suggest that ABCG1 increases the availability of APP as a secretase substrate for both the amyloidogenic and nonamyloidogenic pathways. In vivo, ABCG1 mRNA levels are 2-fold more abundant in DS brain compared with age- and sex-matched normal controls. Finally, both Aß and sAPP levels are increased in DS cortex relative to normal controls. These findings suggest that altered cholesterol metabolism and APP trafficking mediated by ABCG1 may contribute to the accelerated onset of AD neuropathology in DS.

Supplementary key words ATP binding cassette transporter G1 • Alzheimer's disease • amyloid ß proteins • Down syndrome

Abbreviations: Aß, amyloid-ß protein; AD, Alzheimer's disease; apoA-I, apolipoprotein A-I; APP, ß-amyloid precursor protein; CTF, C-terminal fragment; DS, Down syndrome; sAPP, secreted APP

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