Low anticoagulant heparin oligosaccharides as inhibitors of BACE-1, the Alzheimer's β-secretase

Xiao Zhang; Xiaoliang Zhao; Yinzhi Lang; Qinying Li; Xiaoxiao Liu; Chao Cai; Jiejie Hao; Guoyun Li; Guangli Yu

doi:10.1016/j.carbpol.2016.05.050

Low anticoagulant heparin oligosaccharides as inhibitors of BACE-1, the Alzheimer's β-secretase

Carbohydr Polym. 2016 Oct 20:151:51-59. doi: 10.1016/j.carbpol.2016.05.050. Epub 2016 May 17.

Authors

Xiao Zhang¹, Xiaoliang Zhao¹, Yinzhi Lang¹, Qinying Li¹, Xiaoxiao Liu¹, Chao Cai², Jiejie Hao², Guoyun Li³, Guangli Yu⁴

Affiliations

¹ Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
² Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, Ocean University of China, Qingdao 266003, China.
³ Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, Ocean University of China, Qingdao 266003, China. Electronic address: liguoyun@ouc.edu.cn.
⁴ Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237,China. Electronic address: glyu@ouc.edu.cn.

PMID: 27474542
DOI: 10.1016/j.carbpol.2016.05.050

Abstract

Heparin (HP) is a promising agent for anti-Alzheimer's disease (AD), but its anticoagulant activity limits its applications. So a low anticoagulant heparin (LAH) with anti-AD effect is needed. A novel LAH and heparan sulfate (HS) were purified from crude porcine intestinal heparin. Their structures were characterized by nuclear magnetic resonance and liquid chromatography-mass spectrometry. LAH had a relatively high degree of sulfation, but lower than that of HP. 3-O-Sulfated-containing glucosamine residues further confirmed the low anticoagulant activity of LAH. Sixteen oligosaccharides of LAH and HS were prepared and assigned. Evaluation of anti-BACE-1 activities suggested that their potencies were positively correlated with degree of sulfation and polymerization of oligosaccharides. Besides, LAH-derived hexa- to dodecasaccharides was promised to be administrated in vitro as BACE-1 inhibitors. This study presented ideal BACE-1 inhibitors, LAH-derived oligosaccharides, with virtually no anticoagulant activities, which were promised to be excellent leads for treatment of AD.

Keywords: Alzheimer’s disease; Anti-β-secretase-1 activities; Heparan sulfate; Low anticoagulant heparin; Oligosaccharide.

MeSH terms

Alzheimer Disease
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / chemistry
Anticoagulants / chemistry
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / chemistry
Factor Xa / chemistry
Heparin / chemistry*
Oligosaccharides / chemistry*
Prothrombin / chemistry

Substances

Anticoagulants
Oligosaccharides
Prothrombin
Factor IIa
Heparin
Amyloid Precursor Protein Secretases
Factor Xa
Aspartic Acid Endopeptidases
BACE1 protein, human