Histidine-Rich Oligopeptides To Lessen Copper-Mediated Amyloid-β Toxicity

Brain copper imbalance plays an important role in amyloid-beta aggregation, tau hyperphosphorylation, and neurotoxicity observed in Alzheimer's disease (AD). Therefore, the administration of biocompatible metal-binding agents may offer a potential therapeutic solution to target mislocalized copper ions and restore metallostasis. Histidine-containing peptides and proteins are excellent metal binders and are found in many natural systems. The design of short peptides showing optimal binding properties represents a promising approach to capture and redistribute mislocalized metal ions, mainly due to their biocompatibility, ease of synthesis, and the possibility of fine-tuning their metal-binding affinities in order to suppress unwanted competitive binding with copper-containing proteins. In the present study, three peptides, namely HWH, (HKH)-H-C, and HAH, have been designed with the objective of reducing copper toxicity in AD. These tripeptides form highly stable albumin-like complexes, showing higher affinity for Cu-II than that of A beta(1-40). Furthermore, HWH, (HKH)-H-C, and HAH act as very efficient inhibitors of copper-mediated reactive oxygen species (ROS) generation and prevent the copper-induced overproduction of toxic oligomers in the initial steps of amyloid aggregation in the presence of Cu-II ions. These tripeptides, and more generally small peptides including the sequence His-Xaa-His at the N-terminus, may therefore be considered as promising motifs for the future development of new and efficient anti-Alzheimer drugs.