Beta-amyloid peptide (Aβ) is a ligand associated with RAGE (Advanced glycosylation end product-specific receptor). Aβ is translocated in complexes with RAGE from the blood to brain across the blood-brain barrier (BBB) by transcytosis. Aβ and its isoforms are important factors in the Alzheimer's disease (AD) pathogenesis. However, interaction with RAGE was previously studied for Aβ but not for its isoforms. The present study has been directed at identifying the key interaction interfaces between RAGE and Aβ isoforms (Aβ40, Aβ42, phosphorylated and isomerized isoforms pS8-Aβ42, isoD7-Aβ42). Two interfaces have been identified by docking: they are represented by an extended area at the junction of RAGE domains V and C1 and a smaller area linking C1 and C2 domains. Molecular dynamics (MD) simulations have shown that all Aβ isoforms form stable and tightly bound complexes. This indicates that all Aβ isoforms potentially can be transported through the cell as part of a complex with RAGE. Modeling of RAGE interaction interfaces with Aβ indicates which chemical compounds can potentially be capable of blocking this interaction, and impair the associated pathogenic cascades. The ability of three RAGE inhibitors (RAP, FPS-ZM1 and RP-1) to disrupt the RAGE:Aβ interaction has been probed by docking and subsequently the complexes' stability verified by MD. The RP-1 and Aβ interaction areas coincide and therefore this inhibitor is very promising for the RAGE:Aβ interaction inhibition.
Keywords: Alzheimer’s disease; RAGE; beta-amyloid; blood–brain barrier; interaction interface; macromolecular docking; molecular dynamics; transcytosis.