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Journal of Lipid Research, Vol. 49, 1254-1267, June 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo

Braydon L. Burgess^*, Pamela F. Parkinson^*, Margaret M. Racke, Veronica Hirsch-Reinshagen^*, Jianjia Fan^*, Charmaine Wong^*, Sophie Stukas^*, Louise Theroux, Jeniffer Y. Chan^*, James Donkin^*, Anna Wilkinson^*, Danielle Balik^*, Brian Christie^**, Judes Poirier, Dieter Lütjohann, Ronald B. DeMattos and Cheryl L. Wellington^1,*

^* Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, Canada
Lilly Research Laboratories, Indianapolis, IN
McGill Centre for Studies on Aging, Montreal, Canada
^** Division of Medical Sciences, University of Victoria, Victoria, Canada
Department of Clinical Pharmacology, University of Bonn, Bonn, Germany

This study was supported by operating grants from the Alzheimer's Society of Canada (C.L.W.), the American Health Assistance Foundation (C.L.W.), and the Canadian Institutes of Health Research (C.L.W., B.C., J.P.). J.D. is supported by the University of British Columbia Arthur June Williams postdoctoral fellowship. B.C. is a Michael Smith Foundation for Health Research Senior Scholar. C.L.W. is a CIHR New Investigator.

Published, JLR Papers in Press, February 26, 2008.

¹ To whom correspondence should be addressed. e-mail: Cheryl{at}cmmt.ubc.ca

Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Aβ production. To clarify the in vivo roles of ABCG1 in Aβ metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Aβ, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Aβ levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Aβ metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway.

Supplementary key words lipid • central nervous system • ATPase binding cassette transporter

Abbreviations: AD, Alzheimer's disease; apoE, apolipoprotein E; APP, amyloid precursor protein; BAC, bacterial artificial chromosome; BBB, blood-brain barrier; CHO, Chinese hamster ovary; CNS, central nervous system; CSF, cerebrospinal fluid; CTF, C-terminal fragment; HEK, human embryonic kidney; HMG-CoAR, HMG-CoA-reductase; LTP, long-term potentiation; LXR, liver X receptor; mAβ, murine Aβ; NGM, neuron growth media; QRT-PCR, quantitative reverse transcriptase PCR

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