title: Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels.
abstract: The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as β-secretase cleaved C-terminal fragment (β-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Additionally, inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and β-secretase activity. Moreover, addition of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and β-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway associated with ABCA1-mediated reduction in membrane cholesterol levels.
authors.affiliation: Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, 200032 Shanghai, China.
authors.forename: Weigang
authors.initials: W
authors.lastname: Cui
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Wang
authors.forename: Chongchong
authors.initials: C
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Zulin
authors.initials: Z
authors.lastname: Chen
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Peng
authors.forename: Ruixi
authors.initials: R
authors.lastname: Li
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D016282:Aspartic Acid Endopeptidases; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009842:Oligopeptides; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D053764:Presenilin-1; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C509282:Bace1 protein, mouse