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-β peptide (hAβ)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [¹²⁵I]hAβ(1-40) efflux clearance in rats and found it to be 11.0 μL/(min g brain). There were no significant gender differences in the apparent brain-to-blood [¹²⁵I]hAβ(1-40) efflux clearance. The brain-to-blood [¹²⁵I]hAβ(1-40) efflux transport was significantly inhibited by unlabeled hAβ(1-40) and hAβ(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hAβ(1-43) and hAβ(40-1), and was significantly facilitated by hAβ(17-40) by 16.0%, which is one of the major proteolytic fragments of hAβ(1-40) generated by the action of Aβ 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 [¹²⁵I]hAβ(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 hAβ(1-40) elimination from rat brain is mediated by as yet unidentified molecules.