Abstract
ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-β peptide (Aβ). ABCG4 is highly expressed in the brain, but its localization and function at the blood-brain barrier (BBB) level remain unknown. We demonstrate by qRT-PCR and confocal imaging that mouse Abcg4 is expressed in the brain capillary endothelial cells. Modelling studies of the Abcg4 dimer suggested that desmosterol showed thermodynamically favorable binding at the putative sterol-binding site, and this was greater than for cholesterol. Additionally, unbiased docking also showed Aβ binding at this site. Using a novel Abcg4-deficient mouse model, we show that Abcg4 was able to export Aβ and desmosterol at the BBB level and these processes could be inhibited by probucol and L-thyroxine. Our assay also showed that desmosterol antagonized the export of Aβ, presumably as both bind at the sterol-binding site on Abcg4. We show for the first time that Abcg4 may function in vivo to export Aβ at the BBB, in a process that can be antagonized by its putative natural ligand, desmosterol (and possibly cholesterol).
Highlights
ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-β peptide (Aβ)
ABCG4 is expressed in neurons and astrocytes present in the hippocampus, cerebellum and olfactory bulb regions, and has been implicated in sterol trafficking in the central nervous system[17,26,39]
ABCG4 has been detected in ependymal cells from brains taken from non-demented patients and in microglial cells from brains from subjects with Alzheimer’s disease[25,50]
Summary
ABCG4 is an ATP-binding cassette transmembrane protein which has been shown, in vitro, to participate in the cellular efflux of desmosterol and amyloid-β peptide (Aβ). We show for the first time that Abcg[4] may function in vivo to export Aβ at the BBB, in a process that can be antagonized by its putative natural ligand, desmosterol (and possibly cholesterol). ABCB1 and ABCG2, as well as the low density lipoprotein receptor-related protein 1 (LRP1) have been shown to be involved in the BBB efflux of Aβ, though other unidentified transporters are likely to be involved in Aβ export[8,18,32,33]. The aim of this study is to characterize the function of Abcg[4] at the mouse BBB to test the hypothesis that it can export desmosterol and Aβ, and characterize the interplay between these two ligands using an in vivo model
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