Opposing Effects of Cucurbit[7]uril and 1,2,3,4,6-Penta-O-galloyl-?-d-glucopyranose on Amyloid ?25-35 Assembly.
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ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid ? protein (A?) in the brain. The conversion of soluble monomers to amyloid A? 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 A? oligomerization, cucurbit[7]uril (CB[7]) and 1,2,3,4,6-penta-O-galloyl-?-d-glucopyranose (PGG), on early oligomer and fibril formation of the A?25-35 fragment. One and two CB[7] molecules bind to A?25-35 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 A?25-35. The interactions between PGG and A?25-35, surprisingly, enhanced the formation of A? aggregates by promoting extended A?25-35 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 A?25-35 aggregation, suppressing the formation of large amyloid oligomers and eliminating the structural conversion from isotropic to ?-rich topologies induced by PGG. Our results provide mechanistic insights into CB[7] and PGG action on A? oligomerization. They also demonstrate the power of the IMS technique to investigate mechanisms of multiple small-molecule agents on the amyloid formation process.
SUBMITTER: de Almeida NE
PROVIDER: S-EPMC4758880 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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