Transport of Alzheimer's Associated Amyloid‐β Through Membranes Catalyzed by P‐Glycoprotein

Abstract

The broad range of substrates that can be transported by ABCB1 plasma membrane transporters has been well established. Of these transporters, MDR1 P‐glycoprotein (P‐gp), has been extensively studied and is best known for the abilities to confer general multidrug resistance to populations of cancer cells and for preventing pharmaceutical products from crossing the blood brain barrier (BBB). P‐gp action has recently been also implicated in Alzheimer's disease (AD). One of the clearance pathways of amyloid‐β, thought to be a causative agent in neurodegeneration and symptom onset in AD, is suggested to be through P‐gp across the BBB. In this study, a P‐gp model with amyloid‐β bound to drug binding domains was used in targeted molecular dynamics simulation (TMD) of the catalytic cycle. TMD employed four different crystallographic conformations to move the protein through open inside to open outside conformations. Transport of amyloid‐β through the membrane was observed during the putative catalytic cycles. Results suggest that the catalytic cycle resulted in movement of amyloid‐β to P‐gp structures productive for release to the extracellular space. These simulations have elucidated specific molecular interactions between P‐gp and amyloid‐β that result in amyloid‐β transport. Such studies have enabled a detailed and targeted biochemical analysis of amyloid‐β transport through the BBB. This work is supported by NIH NIGMS [Grant 1R15‐GM094771‐01A1] to PDV and JGW, SMU Research Council, SMU Dean's Research Council, the SMU Center for Drug Discovery, Design and Delivery, and the Communities Foundation of Texas, Dallas.