Mycroft-West, Courtney J, Devlin, Anthony J, Cooper, Lynsay C, Procter, Patricia, Miller, Gavin J, Fernig, David G 
ORCID: 0000-0003-4875-4293, Guerrini, Marco, Guimond, Scott E, Lima, Marcelo A, Yates, Edwin A ORCID: 0000-0001-9365-5433 et al (show 1 more authors)
(2019)
Inhibition of BACE1, the beta-secretase implicated in Alzheimer's disease, by a chondroitin sulfate extract from Sardina pilchardus.
NEURAL REGENERATION RESEARCH, 15 (8).
pp. 1546-1553.
|
Text
BACE_2019.pdf - Published Version Download (3MB) | Preview |
Abstract
The pharmaceutical and anticoagulant agent heparin, a member of the glycosaminoglycan family of carbohydrates, has previously been identified as a potent inhibitor of a key Alzheimer's disease drug target, the primary neuronal β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1). The anticoagulant activity of heparin has, however, precluded the repurposing of this widely used pharmaceutical as an Alzheimer's disease therapeutic. Here, a glycosaminoglycan extract, composed predominantly of 4-sulfated chondroitin sulfate, has been isolated from Sardina pilchardus, which possess the ability to inhibit BACE1 (IC<sub>50</sub> [half maximal inhibitory concentration] = 4.8 μg/mL), while displaying highly attenuated anticoagulant activities (activated partial thromboplastin time EC<sub>50</sub> [median effective concentration] = 403.8 μg/mL, prothrombin time EC<sub>50</sub> = 1.3 mg/mL). The marine-derived, chondroitin sulfate extract destabilizes BACE1, determined via differential scanning fluorimetry (ΔT<sub>m</sub> -5°C), to a similar extent as heparin, suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action, which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer's disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | amyloid-beta, aspartyl protease, carbohydrates, galactosaminoglycans, heparan sulfate, heparin, marine polysaccharide, pilchards, sardines, therapeutics |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Mar 2020 10:42 |
| Last Modified: | 14 Mar 2024 22:40 |
| DOI: | 10.4103/1673-5374.274341 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3076774 |
Dimensions
Dimensions
