title: Oxysterols decrease apical-to-basolateral transport of Aß peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells.
abstract: It is known that activation of the liver X receptors (LXRs) by natural or synthetic agonists decreases the amyloid burden and enhances cognitive function in transgenic murine models of Alzheimer's disease (AD). Recent evidence suggests that LXR activation may affect the transport of amyloid ß (Aß) peptides across the blood-brain barrier (the BBB, which isolates the brain from the peripheral circulation). By using a well-characterized in vitro BBB model, we demonstrated that LXR agonists (24S-hydroxycholesterol, 27-hydroxycholesterol and T0901317) modulated the expression of target genes involved in cholesterol homeostasis (such as ATP-binding cassette sub-family A member 1 (ABCA1)) and promoted cellular cholesterol efflux to apolipoprotein A-I and high density lipoproteins. Interestingly, we also observed a decrease in Aß peptide influx across brain capillary endothelial cells, although ABCA1 did not appear to be directly involved in this process. By focusing on others receptors and transporters that are thought to have major roles in Aß peptide entry into the brain, we then demonstrated that LXR stimulation provoked an increase in expression of the ABCB1 transporter (also named P-glycoprotein (P-gp)). Further investigations confirmed ABCB1's involvement in the restriction of Aß peptide influx. Taken as a whole, our results not only reinforce the BBB's key role in cerebral cholesterol homeostasis but also demonstrate the importance of the LXR/ABCB1 axis in Aß peptide influx-highlighting an attractive new therapeutic approach whereby the brain could be protected from peripheral Aß peptide entry.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Saint-Pol
authors.forename: Pietra
authors.initials: P
authors.lastname: Candela
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boucau
authors.forename: Laurence
authors.initials: L
authors.lastname: Fenart
authors.forename: Fabien
authors.initials: F
authors.lastname: Gosselet
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000378:metabolism; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000494:pharmacology*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D002784:Cholesterol; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D013449:Sulfonamides; D014316:Tritium; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C044563:24-hydroxycholesterol; C076996:27-hydroxycholesterol