Neuropathology and Applied Neurobiology

RAGE was also shown to mediate the transport of Ab across the blood–brain barrier (BBB) (Deane et al. 2003). 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.

By virtue of being a transmembrane protein, isolated RAGE is a very insoluble molecule. However, soluble RAGE (sRAGE) can also be produced by recombinant DNA. This molecule, in which the transmembrane domain and cytosolic regions are missing, contains the extracellular V, C and C' Ig-like regions up to residue 342 and conserves all the binding properties of native RAGE.