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

Abstract

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 and Aβ 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 than Aβ , which was possibly due to the N-terminal phenylalanine residue of Aβ . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aβ species.

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation

“…Plaques containing amyloid fibrils are one of the histological hallmarks of Alzheimer’s and Parkinson’s diseases (Lee et al, 1991; Spillantini et al, 1997; Koo et al, 1999). Various strategies have been exploited to interfere with the process of amyloid aggregation by targeting different conformational species, including stabilizing monomers by antibodies (Ladiwala et al, 2012), redirecting monomers to nontoxic off-pathway oligomers by polyphenolic compounds (Ehrnhoefer et al, 2008), accelerating mature fibril formation by fibril binders (Bieschke et al, 2012; Jiang et al, 2013), inhibiting fibril growing by peptide blockers (Seidler et al, 2018), and disrupting amyloid assembly by nanomaterials (Hamley, 2012; Huang et al, 2014; Lee et al, 2014; Li et al, 2018; Han and He, 2018). Many of these strategies show promising inhibitory effects against toxic amyloid aggregation (Härd and Lendel, 2012; Arosio et al, 2014), but so far none has led to clinical drugs because of unsettled issues such as target selectivity, side effects, membrane permeability and penetration of the blood-brain barrier.…”

Rational Design of a Cocktail of Inhibitors against Aβ Aggregation

“…Thus, how to develop effective inhibitors to fight against the aggregation of Aβ becomes a key issue in the study of AD . Application of single inhibitor would only interact with some specific Aβ aggregates and block certain aggregation pathways, which in turn may result in the accumulation of other Aβ species and the activation of bypaths. Furthermore, due to the complex and transient features of Aβ oligomers, it is hard to evaluate whether the remaining species would be still harmful to AD patients.…”

“…We then conducted ThT kinetics assay to test whether these conjugates could inhibit the aggregation of Aβ . 10 μ m Aβ 1‐40 were incubated with 20 μ m ThT and varied concentrations of ASn at 37 °C with continuously shaking.…”

“…Inspired by the successful application of “cocktail” style of mixed drug treatment in AIDS, we speculated that a cocktail of properly mixed Aβ inhibitors would interact with more Aβ aggregates and block more aggregation pathways simultaneously, and thus reduce the amount of various Aβ aggregates at the same time. In order to prepare effective cocktails, we referred to chemical kinetics analysis, which could elucidate the molecular mechanisms of inhibitors quantitatively and thus help to make a rational design . With different inhibitors in‐hand, we can divide them into several groups according to their inhibiting mechanisms.…”

“…To elucidate the inhibitory mechanism of AS1 and AS2, chemical kinetics analysis was performed. In accordance with our previous work, the aggregation of Aβ 1‐40 follows the NES mechanism—a combination of primary nucleation, elongation and surface catalyzed secondary nucleation (Figure ). The corresponding ordinary differential equations (ODEs) model is given in the Supplementary Information.…”