Characterizing Heparin Tetrasaccharides Binding to Amyloid-Beta Peptide

The aggregation of beta-amyloid peptide (A beta) is one potential cause for Alzheimer's disease (AD). Heparin can either promote or inhibit A beta aggregation. The sulfation pattern and chain size determine its binding affinity and its role. Using 2D-NMR analysis and molecular modelling, the binding motif of heparin oligoaccharides to A beta was determined to be HexA-GlcNS-IdoA2S-GlcNS6S. Iduronic acid epimerization and 6-O-sulfation are key factors for the binding affinity, while 3-O-sulfation of Arixtra (heparin pentasaccharide) is not involved in the binding to A beta. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) was used to study the glycosaminoglycan (GAG)-peptide complex and identified V12HHQKL17 as the binding site of GAG at A beta. Furthermore, an MTT assay was applied to evaluate the anti-A beta fibril formation function of heparin tetrasaccharide, and indicated that the heparin tetrasaccharide with the defined sequence represents a promising inhibitor of A beta aggregation.