Inhibition of BACE1, the β-secretase implicated in Alzheimer’s disease, by a chondroitin sulfate extract from Sardina pilchardus
Mark A. Skidmore, Courtney J. Mycroft‐West, AnthonyJ Devlin, Lynsay C. Cooper, Patricia Procter, Gavin J. Miller, DavidG Fernig, Marco Guerrini, ScottE Guimond, Marcelo A. Lima, EdwinA Yates
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 50 [half maximal inhibitory concentration] = 4.8 μg/mL), while displaying highly attenuated anticoagulant activities (activated partial thromboplastin time EC 50 [median effective concentration] = 403.8 μg/mL, prothrombin time EC 50 = 1.3 mg/mL). The marine-derived, chondroitin sulfate extract destabilizes BACE1, determined via differential scanning fluorimetry (ΔT m –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.