Dmd052514 1787..1796

Failure in amyloid-b (Ab) systemic clearance across the liver has been suggested to play a role in Ab brain accumulation and thus to contribute largely to the pathology of Alzheimer’s disease (AD). The purpose of this study was to characterize in vitro the transport mechanisms of Ab40 across the liver using sandwich-cultured primary rat hepatocytes (SCHs) and to determine its biliary clearance (CLbile) and biliary excretion index (BEI%). I-Ab40 BEI% was time dependent and reached steady state at 30 minutes, with an average value of 29.8% and a CLbile of 1.47 ml/min per kilogram of body weight. The role of low-density lipoprotein receptor–related protein1 (LRP1) in mediating the basolateral uptake of I-Ab40 in SCHs was assessed using receptor-associated protein (RAP, 2 mM). A significant reduction in I-Ab40 BEI% and CLbile with RAP was observed, demonstrating a major contribution of LRP1 in mediating hepatic uptake of intact I-Ab40 via transcytosis. Furthermore, activity studies suggested a lower role of receptor for advanced glycation end products (RAGE) in I-Ab40 hepatic uptake. Verapamil (50 mM) and valspodar (20 mM) significantly reduced I-Ab40 BEI%, indicating a role for P-glycoprotein (P-gp) in the biliary excretion of I-Ab40 in SCHs. LRP1and P-gp-mediated I-Ab40 biliary excretion was inducible and increased BEI% by 26% after rifampicin pretreatment. In conclusion, our findings demonstrated that besides LRP1, P-gp and, to a lesser extent, RAGE are involved in I-Ab40 hepatobiliary disposition and support the use of enhancement of Ab hepatic clearance via LRP1 and P-gp induction as a novel therapeutic approach for the prevention and treatment of AD.