Biologically Active Fragment of the Receptor for Advanced Glycation End Products (RAGE) Is Able to Inhibit Oligomerization of the Beta-Amyloid

Abstract

Abstract It was found earlier that the synthetic fragment corresponding to the 60–76 sequence of the extracellular domain of the receptor for advanced glycation end products (RAGE) had a protective effect on animal and cellular models of Alzheimer’s disease. It was proposed that this effect was mediated via the interaction of the peptide with beta-amyloid (Aβ), which was one of the RAGE ligands, by inhibiting the formation of toxic Aβ oligomers. The aim of this study was an application of physicochemical methods to an investigation of the ability of the 60–76 peptide to prevent the Aβ40 oligomerization in solution in comparison with the nonprotective 65–76 truncated peptide. The dynamics of the formation of the Aβ40 fibrils in the presence of the peptides was evaluated using thioflavin T. The relative sizes of oligomers were determined by dynamic light scattering. The peptide binding to Aβ40 was examined by fluorescence titration. We demonstrated by the two methods that the peptide corresponding to the 60–76 sequence of RAGE considerably inhibited (by more than 90%) the formation of oligomers and fibrils of Aβ40 distinct from the 65–76 peptide. In addition, we found that the protective effect of the peptides and their ability to inhibit the Aβ40 oligomerization did not correlate with their binding to the monomeric/tetrameric Aβ40. We confirmed in vitro the hypothesis that the protective activity of the synthetic 60–76 fragment of RAGE was associated with its ability to inhibit the Aβ oligomerization.