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. Wellington¹^,*

^* 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'sSociety 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 BritishColumbia 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 importancefor Alzheimer's disease (AD). Agonists of liver-X-receptors(LXRs) stimulate several genes that regulate cholesterol homeostasis,and synthetic LXR agonists decrease neuropathological and cognitivephenotypes in AD mouse models. The cholesterol transporter ABCG1is LXR-responsive and highly expressed in brain. In vitro, conflictingreports exist as to whether ABCG1 promotes or impedes Aβproduction. To clarify the in vivo roles of ABCG1 in Aβmetabolism and brain cholesterol homeostasis, we assessed neuropathologicaland cognitive outcome measures in PDAPP mice expressing excesstransgenic ABCG1. A 6-fold increase in ABCG1 levels did notalter Aβ, amyloid, apolipoprotein E levels, cholesterolefflux, or cognitive performance in PDAPP mice. Furthermore,endogenous murine Aβ levels were unchanged in both ABCG1-overexpressingor ABCG1-deficient mice. These data argue against a direct rolefor ABCG1 in AD. However, excess ABCG1 is associated with decreasedlevels of sterol precursors and increased levels of SREBP-2and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leadsto the opposite effects. Although functions for ABCG1 in cholesterolefflux and Aβ metabolism have been proposed based on resultswith cellular model systems, the in vivo role of this enigmatictransporter may be largely one of regulating the sterol biosyntheticpathway.

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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