Zhou Xiang, Wang Yuanyuan, Zheng Wei, Deng Guangxiu, Wang Fuyi, Jin Lan
National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao, China.
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems Institute of Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
Front Mol Biosci. 2022 Feb 23;9:824146. doi: 10.3389/fmolb.2022.824146. eCollection 2022.
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.
β-淀粉样肽（Aβ）的聚集是阿尔茨海默病（AD）的一个潜在病因。肝素既能促进也能抑制Aβ聚集。硫酸化模式和链大小决定其结合亲和力及其作用。通过二维核磁共振分析和分子建模，确定肝素寡糖与Aβ的结合基序为HexA-GlcNS-IdoA2S-GlcNS6S。艾杜糖醛酸表异构化和6-O-硫酸化是结合亲和力的关键因素，而法安明（肝素五糖）的3-O-硫酸化不参与与Aβ的结合。氢氘交换质谱（HDX-MS）用于研究糖胺聚糖（GAG）-肽复合物，并确定V12HHQKL17为GAG在Aβ上的结合位点。此外，采用MTT法评估肝素四糖的抗Aβ纤维形成功能，结果表明具有特定序列的肝素四糖是一种很有前景的Aβ聚集抑制剂。
