A specific RAGE-binding peptide biopanning from phage display random peptide library that ameliorates symptoms in amyloid beta peptide-mediated neuronal disorder

Alzheimer's disease (AD) is an age-related neuro-degenerative disorder in which amyloid beta (A beta) peptide accumulates in the brain. The receptor for advanced glycation end product (RAGE) is a cellular binding site for A beta peptide and mediates amyloid beta-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a specific high-affinity RAGE inhibitor (APDTKTQ named RP-1) from a phage display library. RP-1 bound to RAGE and inhibited A beta peptide-induced cellular stress in human neuroblastoma SH-SYSY cells in vitro. Three amino acids in RP-1 are identical to those in the A beta peptide. RP-1 shows high homology to the 16-23 (KLVFFAED) regions in A beta peptide and high-affinity RAGE. Functional analyses indicated that RP-1 significantly reduced the level of reactive oxygen species (ROS) and ROS products and that it enhanced catalase and glutathione peroxidase (GPx) activity. Furthermore, it inactivated caspase3 and caspase9 and inhibited the upregulation of RAGE, nuclear factor-kappa B (NF-kappa B), and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein expression. In addition, RP-1 activated the PI3K/AKT signaling pathway, inhibiting the interaction between Bax and Bcl-2. Our data suggest that RP-1 is a potent RAGE blocker that effectively controls the progression of A beta peptide-mediated brain disorders and that it may have potential as a disease-modifying agent for AD.