Abstract
The aggregation of β-amyloid peptide (Aβ) is one potential cause for Alzheimer’s disease (AD). Heparin can either promote or inhibit Aβ 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 Aβ 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 Aβ. 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 Aβ. Furthermore, an MTT assay was applied to evaluate the anti-Aβ fibril formation function of heparin tetrasaccharide, and indicated that the heparin tetrasaccharide with the defined sequence represents a promising inhibitor of Aβ aggregation.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease that mainly occurs in people over 65 years of age
Three heparin tetrasaccharides 1-3 with different sulfation patterns were prepared by partial enzymatic digestion of heparin, gel permeation chromatography fractionation, and strong anion-exchange liquid chromatography separation (Supplementary Figure S1). 1H spectra were used to characterize the purity based on the signal integration. (Supplementary Figure S3)
The sulfo groups of heparin and heparan sulfate (HS) can be sorted to 2-O-sulfo of the uronic acid residue, 3- and 6O-sulfo at the GlcN residue, and N-sulfo of the GlcN residue
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease that mainly occurs in people over 65 years of age. Amyloid plaques and Tau pathology have been widely accepted as the two hallmarks of AD, and their explicit mechanisms lead to the development of therapies that target the course of the disease. An excess of Aβ can push the equilibrium to amyloid fibrils, and the fibrils infringe the nerve cells and potentially increase the risk of AD. One of them is Aducanumab (Biogen), which has been approved controversially by FDA but rejected by EMA this year, due to its uncertainty of the efficacy. In addition to these protein-based drugs, sulfated oligosaccharides are promising agents to neutralize excess Aβ because they are less costly and capable of passing the blood-brain barrier.
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