A specific RAGE-binding peptide biopanning from phage display random peptide library that ameliorates symptoms in amyloid β peptide-mediated neuronal disorder.
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.
College of Pharmacy, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China.
Cuizan
C
Cai
Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, 510632, Guangzhou, People's Republic of China.
Xiaoyong
X
Dai
College of Pharmacy, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China.
Yujie
Y
Zhu
College of Pharmacy, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China.
Mengyang
M
Lian
Department of Pharmacology, School of Medicine, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China.
Fei
F
Xiao
College of Pharmacy, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China.
Fangyuan
F
Dong
Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, 510632, Guangzhou, People's Republic of China.
Qihao
Q
Zhang
Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, 510632, Guangzhou, People's Republic of China.
Yadong
Y
Huang
College of Pharmacy, Jinan University, 510632, Guangzhou, Guangdong, People's Republic of China. tzhengq@jnu.edu.cn.
Qing
Q
Zheng
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001435:Bacteriophages / Q000378:metabolism; D001665:Binding Sites; D001921:Brain / Q000502:physiology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002374:Catalase / Q000235:genetics; D045744:Cell Line, Tumor; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D009474:Neurons / Q000502:physiology; D009842:Oligopeptides / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D019151:Peptide Library; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; C075222:amyloid beta-protein (1-42); D002374:Catalase; D005979:Glutathione Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D053829:Amyloid Precursor Protein Secretases; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Alzheimer’s disease; Aβ; Phage display; RAGE