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
Scott Guimond firstname.lastname@example.org
Gavin Miller email@example.com
Marcelo Andrade De Lima firstname.lastname@example.org
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|
|Peer Reviewed||Peer Reviewed|
|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|
This file is under embargo until Jan 27, 2024 due to copyright restrictions.
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