1. Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus
- Author
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Marco Guerrini, Anthony J. Devlin, Gavin J. Miller, David G. Fernig, Edwin A. Yates, Courtney J. Mycroft-West, Lynsay C. Cooper, Patricia Procter, Marcelo A. Lima, Mark A. Skidmore, and Scott E. Guimond
- Subjects
0301 basic medicine ,Pharmacology ,Q1 ,lcsh:RC346-429 ,Glycosaminoglycan ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Developmental Neuroscience ,mental disorders ,medicine ,Amyloid precursor protein ,QD ,Chondroitin sulfate ,IC50 ,lcsh:Neurology. Diseases of the nervous system ,RM695_Physical ,medicine.diagnostic_test ,biology ,Heparin ,Heparan sulfate ,amyloid-β ,aspartyl protease ,carbohydrates ,galactosaminoglycans ,heparan sulfate ,heparin ,marine polysaccharide ,pilchards ,sardines ,therapeutics ,R1 ,030104 developmental biology ,chemistry ,H1 ,biology.protein ,Anticoagulant Agent ,030217 neurology & neurosurgery ,medicine.drug ,Partial thromboplastin time - 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\ud 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\ud Alzheimer’s disease therapeutic. Here, a glycosaminoglycan extract, composed predominantly of 4-sulfated\ud chondroitin sulfate, has been isolated from Sardina pilchardus, which possess the ability to inhibit BACE1\ud (IC50 [half maximal inhibitory concentration] = 4.8 μg/mL), while displaying highly attenuated anticoagulant activities (activated partial thromboplastin time EC50 [median effective concentration] = 403.8 μg/mL,\ud prothrombin time EC50 = 1.3 mg/mL). The marine-derived, chondroitin sulfate extract destabilizes BACE1,\ud determined via differential scanning fluorimetry (ΔTm –5°C), to a similar extent as heparin, suggesting that\ud BACE1 inhibition by glycosaminoglycans may occur through a common mode of action, which may assist\ud in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.
- Published
- 2020
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