Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid beta Toxicity

Abstract

Accumulation of amyloid beta (A beta) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrilar aggregates of A beta exhibit different levels of neuronal toxicity. Moreover, aggregation of A beta in the presence of redox-active metal ions like Cu2+ is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of A beta aggregation. It was shown by employing various biophysical studies that P6 interact with A beta and prevent the formation of toxic A beta forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu2+ from the A beta-Cu2+ complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by A beta oligomers and efficiently prevented DNA damage caused by the A beta-Cu2+ complex. PC12 cells were rescued from multifaceted A beta toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted A toxicity in AD.