Opposing Effects of Cucurbit[7]uril and 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose on Amyloid β25–35 Assembly

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 inhibit...