title: Opposing Effects of Cucurbit[7]uril and 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose on Amyloid β25-35 Assembly.
abstract: Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid β protein (Aβ) in the brain. The conversion of soluble monomers to amyloid Aβ fibrils is a complicated process and involves several transient oligomeric species, which are widely believed to be highly toxic and play a crucial role in the etiology of AD. The development of inhibitors to prevent formation of small and midsized oligomers is a promising strategy for AD treatment. In this work, we employ ion mobility spectrometry (IMS), transmission electron microscopy (TEM), and molecular dynamics (MD) simulations to elucidate the structural modulation promoted by two potential inhibitors of Aβ oligomerization, cucurbit[7]uril (CB[7]) and 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG), on early oligomer and fibril formation of the Aβ25-35 fragment. One and two CB[7] molecules bind to Aβ25-35 monomers and dimers, respectively, and suppress aggregation by remodeling early oligomer structures and inhibiting the formation of higher-order oligomers. On the other hand, nonselective binding was observed between PGG and Aβ25-35. The interactions between PGG and Aβ25-35, surprisingly, enhanced the formation of Aβ aggregates by promoting extended Aβ25-35 conformations in both homo- and hetero-oligomers. When both ligands were present, the inhibitory effect of CB[7] overrode the stimulatory effect of PGG on Aβ25-35 aggregation, suppressing the formation of large amyloid oligomers and eliminating the structural conversion from isotropic to β-rich topologies induced by PGG. Our results provide mechanistic insights into CB[7] and PGG action on Aβ oligomerization. They also demonstrate the power of the IMS technique to investigate mechanisms of multiple small-molecule agents on the amyloid formation process.
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Natália E C
authors.initials: NE
authors.lastname: de Almeida
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Tro
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Nichole E
authors.initials: NE
authors.lastname: LaPointe
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Feinstein
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: Department of Chemistry and Biochemistry, ‡Neuroscience Research Institute and Department of Molecular Cellular and Developmental Biology, University of California , Santa Barbara, California 93106, United States.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D016229:Amyloid beta-Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D003198:Computer Simulation; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D013058:Mass Spectrometry; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D016229:Amyloid beta-Peptides; D001952:Bridged-Ring Compounds; D047348:Hydrolyzable Tannins; D007093:Imidazoles; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils; C435084:pentagalloylglucose
keywords: Amyloids; amyloid β; computational modeling; cucurbiturils; ion-mobility mass spectrometry; polyphenols