A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease β-Site amyloid precursor protein cleaving enzyme 1 (BACE-1)

Mycroft-West, Courtney J, Devlin, Anthony J, Cooper, Lynsay C ORCID: 0000-0002-5100-5261, Guimond, Scott E, Procter, Patricia, Miller, Gavin J, Guerrini, Marco, Fernig, David G, Yates, Edwin A, Lima, Marcelo A and Skidmore, Mark A (2023) A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease β-Site amyloid precursor protein cleaving enzyme 1 (BACE-1). Carbohydrate Research, 525. ART 108747. doi:10.1016/j.carres.2023.108747

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12311 Mycroft-West, Devlin, cooper, Guimond, Procter, Miller, Guerrini, Fernig, Yates, Lima, Skidmore (2023) A sulphated glycosaminoglycan extract from Placopecten magellanicus inhibits the Alzheimer's disease.pdf - Accepted Version
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Abstract

The clinically important anticoagulant heparin, a member of the glycosaminoglycan family of carbohydrates that is extracted predominantly from porcine and bovine tissue sources, has previously been shown to inhibit the β-Site amyloid precursor protein cleaving enzyme 1 (BACE-1), a key drug target in Alzheimer's Disease. In addition, heparin has been shown to exert favourable bioactivities through a number of pathophysiological pathways involved in the disease processes of Alzheimer's Disease including inflammation, oxidative stress, tau phosphorylation and amyloid peptide generation. Despite the multi-target potential of heparin as a therapeutic option for Alzheimer's disease, the repurposing of this medically important biomolecule has to-date been precluded by its high anticoagulant potential. An alternative source to mammalian-derived glycosaminoglycans are those extracted from marine environments and these have been shown to display an expanded repertoire of sequence-space and heterogeneity compared to their mammalian counterparts. Furthermore, many marine-derived glycosaminoglycans appear to retain favourable bioactivities, whilst lacking the high anticoagulant potential of their mammalian counterparts. Here we describe a sulphated, marine-derived glycosaminoglycan extract from the Atlantic Sea Scallop, Placopecten magellanicus that displays high inhibitory potential against BACE-1 (IC50 = 4.8 g.mL−1) combined with low anticoagulant activity; 25-fold less than that of heparin. This extract possesses a more favourable therapeutic profile compared to pharmaceutical heparin of mammalian provenance and is composed of a mixture of heparan sulphate (HS), with a high content of 6-sulphated N-acetyl glucosamine (64%), and chondroitin sulphate.

Item Type: Article
Article Type: Article
Uncontrolled Keywords: Alzheimer's disease; Amyloid-β; BACE-1; β-secretase; β-Site amyloid precursor protein cleaving enzyme 1; Glycosaminoglycan; Chondroitin sulphate; Heparin; Heparan sulphate; Placopecten magellanicus
Subjects: Q Science > QD Chemistry
R Medicine > R Medicine (General)
Divisions: Schools and Research Institutes > School of Education and Science
Research Priority Areas: Place, Environment and Community
Depositing User: Anna Kerr
Date Deposited: 10 Feb 2023 09:56
Last Modified: 31 Aug 2023 08:57
URI: https://eprints.glos.ac.uk/id/eprint/12311

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