Mycroft-West, CJ, Devlin, AJ, Cooper, LC, Procter, P, Miller, GJ, Fernig, DG, Guerrini, M, Guimond, SE, Lima, MA, Yates, EA and Skidmore, MA (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). 1546 - 1553. ISSN 1673-5374

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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
Additional Information: Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.
Uncontrolled Keywords: bace1, β-secretase, Alzheimer's disease, chondroitin sulfate extract, Sardina pilchardus.
Subjects: H Social Sciences > H Social Sciences (General)
Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Natural Sciences > School of Life Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 05 Feb 2020 14:43
Last Modified: 05 Feb 2020 14:43

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