Amyloid-beta (A beta) 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 A beta peptide from circulating blood to human brain, and also causes the activation of the NF-kappa B signaling pathway. Here we show that two beta-strands of RAGE participate in the interaction with A beta peptide. Serial deletion analysis of the RAGE V domain indicates that the third and eighth beta-strands are required for interaction with A beta peptide. Site-directed mutagenesis of amino acids located in the third and eighth beta-strands abolish the interaction of RAGE with A beta peptide. Wild-type RAGE activates the NF-kappa B signaling pathway in response to A beta peptide treatment, while a RAGE mutant defective in A beta binding does not. Furthermore, use of peptide for the third beta-strand or a RAGE monoclonal antibody that targets the RAGE-A beta interaction interface inhibited transport of the A beta 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. (C) 2013 Elsevier Inc. All rights reserved.