Characterizing Heparin Tetrasaccharides Binding to Amyloid-Beta Peptide.

ABSTRACT

The aggregation of ß-amyloid peptide (Aß) is one potential cause for Alzheimer's disease (AD). Heparin can either promote or inhibit Aß 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 Aß 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 Aß. 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 Aß. Furthermore, an MTT assay was applied to evaluate the anti-Aß fibril formation function of heparin tetrasaccharide, and indicated that the heparin tetrasaccharide with the defined sequence represents a promising inhibitor of Aß aggregation.