Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Adenosine Triphosphate / metabolism
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Alzheimer Disease / metabolism*
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Amyloid beta-Peptides / chemistry
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Amyloid beta-Peptides / metabolism*
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Biocatalysis
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Blood-Brain Barrier / metabolism
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Cell Line, Tumor
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Disease Progression
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Humans
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Hydrolysis
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Ligands
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Molecular Docking Simulation
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Molecular Dynamics Simulation
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Peptide Fragments / chemistry
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Peptide Fragments / metabolism*
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Protein Binding
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Protein Conformation, beta-Strand
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Protein Domains
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Protein Transport
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Quinolines / pharmacology
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Signal Transduction / drug effects
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Substrate Specificity
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Amyloid beta-Peptides
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Ligands
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Peptide Fragments
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Quinolines
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amyloid beta-protein (1-40)
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amyloid beta-protein (1-42)
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Adenosine Triphosphate
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tariquidar