Neural Regeneration Research ›› 2020, Vol. 15 ›› Issue (8): 1546-1553.doi: 10.4103/1673-5374.274341

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Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus

Courtney J. Mycroft-West1 , Anthony J. Devlin1 , Lynsay C. Cooper1 , Patricia Procter1 , Gavin J. Miller2 , David G. Fernig3 , Marco Guerrini4 , Scott E. Guimond5, 1, 3, Marcelo A. Lima1 , Edwin A. Yates3, 1, Mark Andrew Skidmore1, 3, 5, *   

  1. 1 Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire, ST5 5BG, UK 2 Lennard-Jones Laboratory, School of Chemical and Physical Sciences, Keele University, Keele, Staffordshire, ST5 5BG, UK 3 Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK 4 Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milan, Italy 5 School of Medicine, Keele, Staffordshire, ST5 5BG, UK
  • Online:2020-08-15 Published:2020-09-16
  • Contact: Mark Andrew Skidmore, PhD, m.a.skidmore@keele.ac.uk.
  • Supported by:
    This study was financially supported by grants from the Engineering and Physical Sciences Research Council, UK, the Biotechnology and Biological Sciences Research Council, UK, the Medical Research Council, UK, Intellihep Ltd., UK, MI Engineering Ltd., UK and Financiadora de Estudos e Projetos.

Abstract: The pharmaceutical and anticoagulant agent heparin, a member of the glycosaminoglycan family of carbohydrates, has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target, the primary neuronal β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1). The anticoagulant activity of heparin has, however, precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic. Here, a glycosaminoglycan extract, composed predominantly of 4-sulfated chondroitin sulfate, has been isolated from Sardina pilchardus, which possess the ability to inhibit BACE1 (IC50 [half maximal inhibitory concentration] = 4.8 μg/mL), while displaying highly attenuated anticoagulant activities (activated partial thromboplastin time EC50 [median effective concentration] = 403.8 μg/mL, prothrombin time EC50 = 1.3 mg/mL). The marine-derived, chondroitin sulfate extract destabilizes BACE1, determined via differential scanning fluorimetry (ΔTm –5°C), to a similar extent as heparin, suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action, which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.

Key words: amyloid-β, aspartyl protease, carbohydrates, galactosaminoglycans, heparan sulfate, heparin, marine polysaccharide, pilchards, sardines, therapeutics