title: Enhanced brain amyloid-β clearance by rifampicin and caffeine as a possible protective mechanism against Alzheimer's disease.
abstract: Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer's disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ± 6.1%, p < 0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD.
authors.affiliation: Department of Basic Pharmaceutical Science, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
authors.forename: Hisham
authors.initials: H
authors.lastname: Qosa
authors.forename: Alaa H
authors.initials: AH
authors.lastname: Abuznait
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Hill
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002110:Caffeine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D007444:Inulin / Q000493:pharmacokinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D012333:RNA, Messenger; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42); D002110:Caffeine; D007444:Inulin; D012293:Rifampin