Functional characterization of the brain-to-blood efflux clearance of human amyloid-β peptide (1-40) across the rat blood-brain barrier

The present study sought to characterize the brain-to-blood efflux transport of human amyloid-P peptide (hA beta)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [I-125]hA beta(1-40) efflux clearance in rats and found it to be 11.0 mu L/(min g brain). There were no significant gender differences in the apparent brain-to-blood [I-125]hA beta(1-40) efflux clearance. The brain-to-blood [I-125]hA beta(1-40) efflux transport was significantly inhibited by unlabeled hA beta(1-40) and hA beta(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hA beta(1-43) and hA beta(40-1), and was significantly facilitated by hA beta(17-40) by 16.0%, which is one of the major proteolytic fragments of hA beta(1-40) generated by the action of A beta 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 [I-125]hA beta(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 hA beta(1-40) elimination from rat brain is mediated by as yet unidentified molecules. (c) 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.