Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation

Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-b (Aβ) peptides, primarily Aβ (1-40) and Aβ (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Aβ, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed α,β-dehydroalanine (ΔAla)-containing peptides P1 (K-L-V-F-ΔA-I-ΔA) and P2 (K-F-ΔA-ΔA-ΔA-F) to inhibit Aβ (1-42) aggregation. The mechanism of interaction of the two peptides with Aβ (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of ΔAla-containing peptides as tools to disrupt Aβ aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.