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

• A novel and natural low anticoagulant heparin (LAH) was isolated and purified.
• Low molecular weight derivatives of LAH were prepared and characterized.
• Relationship between structure and anti-BACE-1 activities of samples was elucidated.
• Hexa- to dodecasaccharides were promised to be administrated as BACE-1 inhibitors.
• LAH-derived oligosaccharides were promised to be excellent leads for treatment of AD.

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.