Abstract
Failure in amyloid beta (Aβ) systemic clearance across the liver has been suggested to play a role in Aβ brain accumulation and thus contributes largely to Alzheimer's disease (AD) pathology. The purpose of this study was to in vitro characterize the transport mechanisms of Aβ40 across the liver using sandwich cultured primary rat hepatocytes (SCHs) and determine its biliary clearance (Clbile) and biliary excretion index (BEI%). 125I-Aβ40 BEI% was time dependent and reached steady state at 30min with an average value of 29.8% and Clbile of 1.47ml/min/kg. The role of low density lipoprotein-receptor related protein-1 (LRP1) in mediating the basolateral uptake of 125I-Aβ40 in SCHs was assessed using receptor-associated protein (RAP, 2μM). Significant reduction in 125I-Aβ40 BEI% and Clbile with RAP was observed, demonstrating a major contribution of LRP1 in mediating hepatic uptake of intact 125I-Aβ40 via transcytosis. Furthermore, activity studies suggested lower role of receptor for advanced glycation end products (RAGE) in 125I-Aβ40 hepatic uptake. Verapamil (50μM) and valspodar (20μM) significantly reduced 125I-Aβ40 BEI% indicating a role for P-glycoprotein (P-gp) in the biliary excretion of 125I-Aβ40 in SCHs. LRP1 and P-gp mediated 125I-Aβ40 biliary excretion was inducible and increased BEI% by 26% following rifampicin pretreatment. In conclusion, our findings demonstrated that beside LRP1, P-gp and to a lesser extent RAGE are involved in 125I-Aβ40 hepatobiliary disposition, and support that enhancement of Aβ hepatic clearance via LRP1 and P-gp induction as a novel therapeutic approach for AD prevention and treatment.
- ABC transporters
- active transport
- hepatic transport
- hepatic uptake
- hepatocytes
- induction
- inhibition
- kinetics
- p-glycoprotein
- The American Society for Pharmacology and Experimental Therapeutics