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

• Main Authors: Courtney J Mycroft-West, Anthony J Devlin, Lynsay C Cooper, Patricia Procter, Gavin J Miller, David G Fernig, Marco Guerrini, Scott E Guimond, Marcelo A Lima, Edwin A Yates, Mark Andrew Skidmore
• Format: Article
• Language: English
• Published: Wolters Kluwer Medknow Publications 2020-01-01
• Series: Neural Regeneration Research
• Subjects: amyloid-β; aspartyl protease; carbohydrates; galactosaminoglycans; heparan sulfate; heparin; marine polysaccharide; pilchards; sardines; therapeutics
• Online Access: http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=8;spage=1546;epage=1553;aulast=Mycroft-West

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.