Rationally Designed Dehydroalanine (Delta Ala)-Containing Peptides Inhibit Amyloid-beta (A beta) Peptide Aggregation

摘要

Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-beta (A beta) peptides, primarily A beta (1-40) and A beta (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 A beta, 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 alpha,beta-dehydroalanine (Delta Ala)-containing peptides P1 (K-L-V-F-Delta A-I-Delta A) and P2 (K-F-Delta A-Delta A-Delta A-F) to inhibit A beta (1-42) aggregation. The mechanism of interaction of the two peptides with A beta (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of Delta Ala-containing peptides as tools to disrupt A beta aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.