title: Two β-strands of RAGE participate in the recognition and transport of amyloid-β peptide across the blood brain barrier.
abstract: Amyloid-β (Aβ) peptide is central to the development of brain pathology in Alzheimer disease (AD) patients. Association with receptors for advanced glycation end-products (RAGE) enables the transport of Aβ peptide from circulating blood to human brain, and also causes the activation of the NF-κB signaling pathway. Here we show that two β-strands of RAGE participate in the interaction with Aβ peptide. Serial deletion analysis of the RAGE V domain indicates that the third and eighth β-strands are required for interaction with Aβ peptide. Site-directed mutagenesis of amino acids located in the third and eighth β-strands abolish the interaction of RAGE with Aβ peptide. Wild-type RAGE activates the NF-κB signaling pathway in response to Aβ peptide treatment, while a RAGE mutant defective in Aβ binding does not. Furthermore, use of peptide for the third β-strand or a RAGE monoclonal antibody that targets the RAGE-Aβ interaction interface inhibited transport of the Aβ peptide across the blood brain barrier in a mice model. These results provide information crucial to the development of RAGE-derived therapeutic reagents for Alzheimer disease.
authors: Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Sun-Jick
authors: SJ
authors: Kim
authors: Jang-Won
authors: JW
authors: Ahn
authors: Hee
authors: H
authors: Kim
authors: Hee-Jin
authors: HJ
authors: Ha
authors: Sang-Woo
authors: SW
authors: Lee
authors: Hyun-Kuk
authors: HK
authors: Kim
authors: Sangho
authors: S
authors: Lee
authors: Hyun-Seok
authors: HS
authors: Hong
authors: Young Ho
authors: YH
authors: Kim
authors: Cheol Yong
authors: CY
authors: Choi
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000276:immunology; D060066:Protein Interaction Maps; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: Alzheimer’s disease; Aβ; RAGE; β-Strand