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

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder in which amyloid β (Aβ) peptide accumulates in the brain. The receptor for advanced glycation end product (RAGE) is a cellular binding site for Aβ peptide and mediates amyloid β-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 Aβ peptide-induced cellular stress in human neuroblastoma SH-SYSY cells in vitro. Three amino acids in RP-1 are identical to those in the Aβ peptide. RP-1 shows high homology to the 16-23 (KLVFFAED) regions in Aβ 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-κB (NF-κB), 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 Aβ peptide-mediated brain disorders and that it may have potential as a disease-modifying agent for AD.

Entropy is a Simple Measure of the Antibody Profile and is an Indicator of Health Status: A Proof of Concept

“…Cancer signatures are distinct by type and from infections 32 , 33 . A tumor presumably presents more antigens, including neo-antigens, to the immune system and is often subject to immune suppression 34 – 37 .…”

In�vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system

“…FPS-ZM1 directly inhibited primary tumor growth; in addition, it blocked RAGE signaling in tumor-associated macrophages, inhibited tumor angiogenesis and inflammatory cell recruitment and inhibited metastasis to the lungs and liver (16). Another RAGE-binding peptide, RP-1, was demonstrated to inhibit Aβ-induced cellular stress in human neuroblastoma cells in vitro (43). Furthermore, Han et al (44) reported that 4,6-bisphenyl-2-(3-alkoxyanilino) pyrimidine inhibited the binding of Aβ to RAGE.…”

Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms

“…These cytokines are observed to increase accumulation of amyloid β-protein in AD by two mechanisms: (1) increased levels of pro-inflammatory cytokines inhibit phagocytosis of amyloid β-protein in AD brains thereby hindering the removal of plaque by resident microglia; (2) TNF has been shown to upregulate the production of amyloid β-protein via activation of the c-Jun N-terminal kinase (JNK)-dependent MAPK pathway, which promotes phosphorylation and cleavage of APP ( Liaoi et al, 2004 ; McAlpine and Tansey, 2008 ; Colombo et al, 2009 ; Montgomery et al, 2011 ; Cheng et al, 2014 ; Ahn et al, 2016 ; Decourt et al, 2017 ; Zhang et al, 2019 ). In addition, activation of the NF-κB pathway further increases BACE expression, resulting in increased production of amyloid β-protein ( Guglielmotto et al, 2012 ; Cai et al, 2016 ). High levels of amyloid β-protein cause IR downregulation via internalization, desensitization or direct substrate competition, which ultimately turn into insulin resistance ( Xie et al, 2002 ; Mullins et al, 2017 ).…”