Differential Modulation of the Aggregation of N-Terminal Truncated Aβ using Cucurbiturils

Modulating the aggregation of Aβ has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aβ species, including N-terminal truncated or/and modified Aβ, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aβ species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aβ_4-40 and Aβ_1-40 through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aβ_4-40 than Aβ_1-40 , which was possibly due to the N-terminal phenylalanine residue of Aβ_4-40 . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aβ species.