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Neural Regen Res. 2020 Aug;15(8):1546-1553. doi: 10.4103/1673-5374.274341.

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

Author information

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; Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire, ST5 5BG; Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK.
6
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB; Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire, ST5 5BG, UK.
7
Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire, ST5 5BG; Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool, L69 7ZB; School of Medicine, Keele, Staffordshire, ST5 5BG, UK.

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.

KEYWORDS:

amyloid-β; aspartyl protease; carbohydrates; galactosaminoglycans; heparan sulfate; heparin; marine polysaccharide; pilchards; sardines; therapeutics

PMID:
31997821
DOI:
10.4103/1673-5374.274341
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