TY - JOUR T1 - Transport of Alzheimer’s Associated Amyloid-β Catalyzed by P-glycoprotein JF - bioRxiv DO - 10.1101/2020.10.22.350777 SP - 2020.10.22.350777 AU - James W. McCormick AU - Lauren Ammerman AU - Gang Chen (党陈) AU - Pia D. Vogel AU - John G. Wise Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/28/2020.10.22.350777.abstract N2 - P-glycoprotein (P-gp) is a critical membrane transporter in the blood brain barrier (BBB) and is implicated in Alzheimer’s disease (AD). However, previous studies on the ability of P-gp to directly transport the Alzheimer’s associated amyloid-β (Aβ) protein have produced contradictory results. Here we use molecular dynamics (MD) simulations, transport substrate accumulation studies in cell culture, and biochemical activity assays to show that P-gp actively transports Aβ. We observed transport of Aβ40 and Aβ42 monomers by P-gp in explicit MD simulations of a putative catalytic cycle. In in vitro assays with P-gp overexpressing cells, we observed enhanced accumulation of fluorescently labeled Aβ42 in the presence of Tariquidar, a potent P-gp inhibitor. We also showed that Aβ42 stimulated the ATP hydrolysis activity of isolated P-gp in nanodiscs. Our findings expand the substrate profile of P-gp, and suggest that P-gp may contribute to the onset and progression of AD.Competing Interest StatementThe authors have declared no competing interest. ER -