title: ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.
abstract: 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 Abeta production. To clarify the in vivo roles of ABCG1 in Abeta 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 Abeta, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Abeta 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 Abeta 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Braydon L
authors.initials: BL
authors.lastname: Burgess
authors.forename: Pamela F
authors.initials: PF
authors.lastname: Parkinson
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Racke
authors.forename: Veronica
authors.initials: V
authors.lastname: Hirsch-Reinshagen
authors.forename: Jianjia
authors.initials: J
authors.lastname: Fan
authors.forename: Charmaine
authors.initials: C
authors.lastname: Wong
authors.forename: Sophie
authors.initials: S
authors.lastname: Stukas
authors.forename: Louise
authors.initials: L
authors.lastname: Theroux
authors.forename: Jeniffer Y
authors.initials: JY
authors.lastname: Chan
authors.forename: James
authors.initials: J
authors.lastname: Donkin
authors.forename: Anna
authors.initials: A
authors.lastname: Wilkinson
authors.forename: Danielle
authors.initials: D
authors.lastname: Balik
authors.forename: Brian
authors.initials: B
authors.lastname: Christie
authors.forename: Judes
authors.initials: J
authors.lastname: Poirier
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Demattos
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001483:Base Sequence; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D008074:Lipoproteins / Q000502:physiology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D017931:DNA Primers; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol