Functional characterization of the brain-to-blood efflux clearance of human amyloid-beta peptide (1-40) across the rat blood-brain barrier.
The present study sought to characterize the brain-to-blood efflux transport of human amyloid-beta peptide (hAbeta)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [(125)I]hAbeta(1-40) efflux clearance in rats and found it to be 11.0 microL/(ming brain). There were no significant gender differences in the apparent brain-to-blood [(125)I]hAbeta(1-40) efflux clearance. The brain-to-blood [(125)I]hAbeta(1-40) efflux transport was significantly inhibited by unlabeled hAbeta(1-40) and hAbeta(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hAbeta(1-43) and hAbeta(40-1), and was significantly facilitated by hAbeta(17-40) by 16.0%, which is one of the major proteolytic fragments of hAbeta(1-40) generated by the action of Abeta degradation enzymes, such as endothelin-converting enzyme. Pre-administration of human receptor-associated protein, a low-density lipoprotein receptor-related protein (LRP) antagonist, reduced the elimination of [(125)I]hAbeta(1-40) by 20.3%, while quinidine or verapamil, P-glycoprotein (P-gp) inhibitors, did not significantly affect the elimination. Western blot analysis suggested that LRP-1 is expressed in rat brain capillary endothelial cells. In conclusion, the partial contribution of LRP-1 and the minor contribution of P-gp suggest that the hAbeta(1-40) elimination from rat brain is mediated by as yet unidentified molecules.
Ito
Shingo
S
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Sendai 980-8578, Japan.
Ohtsuki
Sumio
S
Terasaki
Tetsuya
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D007456:Iodine Isotopes; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; C078592:amyloid beta-protein (1-40)