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

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...

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Vydané v:	Carbohydrate research Ročník 525; s. 108747
Hlavní autori:	Mycroft-West, Courtney J., Devlin, Anthony J., Cooper, Lynsay C., Guimond, Scott E., Procter, Patricia, Miller, Gavin J., Guerrini, Marco, Fernig, David G., Yates, Edwin A., Lima, Marcelo A., Skidmore, Mark A.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Netherlands Elsevier Ltd 01.03.2023
Predmet:	Alzheimer disease Alzheimer Disease - drug therapy Alzheimer's disease amyloid Amyloid beta-Peptides Amyloid beta-Protein Precursor - metabolism Amyloid beta-Protein Precursor - therapeutic use Amyloid Precursor Protein Secretases Amyloid-β Animals anticoagulant activity anticoagulants Anticoagulants - chemistry BACE-1 Cattle chondroitin sulfate Chondroitin sulphate enzymes family glucosamine Glycosaminoglycan Glycosaminoglycans - pharmacology heparan sulfate Heparan sulphate Heparin Heparin - pharmacology inflammation Mammals - metabolism oxidative stress Pectinidae - metabolism peptides phosphorylation Placopecten magellanicus provenance Swine therapeutics β-secretase β-site amyloid precursor protein cleaving enzyme 1 β-site amyloid precursor protein cleaving enzyme 1 Placopecten magellanicus Heparan sulphate BACE-1 β-secretase Glycosaminoglycan Amyloid-β Chondroitin sulphate Heparin Alzheimer's disease
ISSN:	0008-6215, 1873-426X, 1873-426X
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Shrnutí:	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 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. [Display omitted] •A GAG extract from the Atlantic Sea Scallop, P. magellanicus, inhibits BACE-1, a key drug-target in Alzheimer's disease.•The GAG extract is predominantly HS, containing a high content of UA-GlcNAc(6S), uncommon in mammalian-derived HS.•The GAG extract possesses highly attenuated anticoagulant potential compared to mammalian-derived heparin.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-6215 1873-426X 1873-426X
DOI:	10.1016/j.carres.2023.108747