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

Mycroft-West, CJ; Devlin, AJ; Cooper, LC; Guimond, S; Procter, P; Miller, G; Guerrini, M; Fernig, DG; Yates, EA; Andrade De Lima, M; Skidmore, M

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 ß-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 µg.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.

• Journal Article Type: Article
• Acceptance Date: Jan 19, 2023
• Online Publication Date: Jan 26, 2023
• Publication Date: Mar 1, 2023
• Publicly Available Date: Jan 27, 2024
• Journal: Carbohydrate Research
• Print ISSN: 0008-6215
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 525
• Article Number: 108747
• DOI: https://doi.org/10.1016/j.carres.2023.108747
• Keywords: Alzheimer?s disease; Amyloid-0; BACE-1; 0-secretase; 0-site amyloid precursor protein cleaving; enzyme 1; Glycosaminoglycan; Chondroitin sulphate; Heparin; Heparan sulphate; Placopecten magellanicus
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0008621523000095?via%3Dihub