ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo.
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.
Burgess
Braydon L
BL
Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
Parkinson
Pamela F
PF
Racke
Margaret M
MM
Hirsch-Reinshagen
Veronica
V
Fan
Jianjia
J
Wong
Charmaine
C
Stukas
Sophie
S
Theroux
Louise
L
Chan
Jeniffer Y
JY
Donkin
James
J
Wilkinson
Anna
A
Balik
Danielle
D
Christie
Brian
B
Poirier
Judes
J
Lütjohann
Dieter
D
Demattos
Ronald B
RB
Wellington
Cheryl L
CL
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
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