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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Bibliographic Details
Published in:Carbohydrate research Vol. 525; p. 108747
Main Authors: 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.
Format: Journal Article
Language:English
Published: Netherlands Elsevier Ltd 01.03.2023
Subjects:
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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Summary: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.
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ISSN:0008-6215
1873-426X
1873-426X
DOI:10.1016/j.carres.2023.108747