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

Skidmore, Mark Andrew, Mycroft-West, Courtney J., Devlin, Anthony J., Cooper, Lynsay C ORCID: 0000-0002-5100-5261, Procter, Patricia, Miller, Gavin J., Fernig, David G., Guerrini, Marco, Guimond, Scott E., Lima, Marcelo A. and Yates, Edwin A. (2020) Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus. Neural Regeneration Research, 15 (8). p. 1546. doi:10.4103/1673-5374.274341

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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.

Item Type: Article
Article Type: Article
Uncontrolled Keywords: Amyloid-β; Aspartyl protease; Carbohydrates; Galactosaminoglycans; Heparan sulfate; Heparin; Marine polysaccharide; Pilchards; Sardines; Therapeutics
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology > RM695 Physical medicine. physical therapy including massage, exercise, occupational therapy, hydrotherapy, phototherapy, radiotherapy, thermotherapy, electrotherapy
Divisions: Schools and Research Institutes > School of Natural & Social Sciences > Environmental Sciences
Research Priority Areas: Place, Environment and Community
Depositing User: Lynsay Cooper
Date Deposited: 24 Aug 2021 14:54
Last Modified: 24 Aug 2021 15:00
URI: http://eprints.glos.ac.uk/id/eprint/10068

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