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A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease

1
Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UK
2
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milan, Italy
3
Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire ST5 5BG, UK
4
School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
*
Author to whom correspondence should be addressed.
Mar. Drugs 2019, 17(5), 293; https://doi.org/10.3390/md17050293
Received: 18 April 2019 / Revised: 8 May 2019 / Accepted: 9 May 2019 / Published: 16 May 2019
(This article belongs to the Special Issue Marine Glycobiology, Glycomics and Lectins)
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Abstract

Therapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer’s disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab Portunus pelagicus, was identified to inhibit human BACE1 with comparable bioactivity to that of mammalian heparin (IC50 = 1.85 μg mL−1 (R2 = 0.94) and 2.43 μg mL−1 (R2 = 0.93), respectively), while possessing highly attenuated anticoagulant activities. The results from several structural techniques suggest that the interactions between BACE1 and the extract from P. pelagicus are complex and distinct from those of heparin. View Full-Text
Keywords: Alzheimer’s disease; amyloid-β; BACE1; β-secretase; glycosaminoglycan; heparan sulphate; heparin; Portunus pelagicus Alzheimer’s disease; amyloid-β; BACE1; β-secretase; glycosaminoglycan; heparan sulphate; heparin; Portunus pelagicus
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Mycroft-West, C.J.; Cooper, L.C.; Devlin, A.J.; Procter, P.; Guimond, S.E.; Guerrini, M.; Fernig, D.G.; Lima, M.A.; Yates, E.A.; Skidmore, M.A. A Glycosaminoglycan Extract from Portunus pelagicus Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease. Mar. Drugs 2019, 17, 293.

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