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

In the AD brain, there are elevated amounts of soluble and insoluble Aβ peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Aβ to soluble RAGE inhibits further aggregation of Aβ peptides, while membrane bound RAGE-Aβ interactions elicit activation of the NF-κB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Aβ, is a powerful inhibitor of Aβ polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Aβ 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 Aβ dock.