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

Mycroft-West, Courtney J.; Devlin, Anthony J.; Cooper, Lynsay C.; Procter, Patricia; Miller, Gavin J.; Fernig, David G.; Guerrini, Marco; Guimond, Scott E.; Lima, Marcelo A.; Yates, Edwin A.; Skidmore, Mark Andrew

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 ß-secretase, ß-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 (?Tm -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.

Citation

Mycroft-West, C. J., Devlin, A. J., Cooper, L. C., Procter, P., Miller, G. J., Fernig, D. G., …Skidmore, M. A. (2020). Inhibition of BACE1, the ß-secretase implicated in Alzheimer's disease, by a chondroitin sulfate extract from Sardina pilchardus. Neural Regeneration Research, 15(8), 1546 - 1553. https://doi.org/10.4103/1673-5374.274341

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2019
• Publication Date: Jan 28, 2020
• Journal: Neural Regeneration Research
• Print ISSN: 1673-5374
• Publisher: Medknow Publications
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 8
• Pages: 1546 - 1553
• DOI: https://doi.org/10.4103/1673-5374.274341
• Keywords: bace1, ß-secretase, Alzheimer's disease, chondroitin sulfate extract, Sardina pilchardus.
• Publisher URL: http://www.nrronline.org/article.asp?issn=1673-5374;year=2020;volume=15;issue=8;spage=1546;epage=1553;aulast=Mycroft%2DWest