RAGE and amyloid beta interactions: Atomic force microscopy and molecular modeling

In the AD brain, there are elevated amounts of soluble and insoluble A beta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble A beta to soluble RAGE inhibits further aggregation of A beta peptides, while membrane bound RAGE-A beta interactions elicit activation of the NF-kappa B transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with A beta, is a powerful inhibitor of A beta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-A beta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric A beta dock. (c) 2005 Elsevier B.V. All rights reserved.