A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease
Therapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant ^...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-05-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1660-3397/17/5/293 |
| _version_ | 1818015389128327168 |
|---|---|
| author | Courtney J. Mycroft-West Lynsay C. Cooper Anthony J. Devlin Patricia Procter Scott E. Guimond Marco Guerrini David G. Fernig Marcelo A. Lima Edwin A. Yates Mark A. Skidmore |
| author_facet | Courtney J. Mycroft-West Lynsay C. Cooper Anthony J. Devlin Patricia Procter Scott E. Guimond Marco Guerrini David G. Fernig Marcelo A. Lima Edwin A. Yates Mark A. Skidmore |
| author_sort | Courtney J. Mycroft-West |
| collection | DOAJ |
| description | Therapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer’s disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab <i>Portunus pelagicus</i>, was identified to inhibit human BACE1 with comparable bioactivity to that of mammalian heparin (IC<sub>50</sub> = 1.85 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.94) and 2.43 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.93), respectively), while possessing highly attenuated anticoagulant activities. The results from several structural techniques suggest that the interactions between BACE1 and the extract from <i>P. pelagicus</i> are complex and distinct from those of heparin. |
| first_indexed | 2024-04-14T06:57:12Z |
| format | Article |
| id | doaj.art-9b0212c58018467d8dc0b138c8469987 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-14T06:57:12Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-9b0212c58018467d8dc0b138c84699872022-12-22T02:06:52ZengMDPI AGMarine Drugs1660-33972019-05-0117529310.3390/md17050293md17050293A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s DiseaseCourtney J. Mycroft-West0Lynsay C. Cooper1Anthony J. Devlin2Patricia Procter3Scott E. Guimond4Marco Guerrini5David G. Fernig6Marcelo A. Lima7Edwin A. Yates8Mark A. Skidmore9Molecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKIstituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Via G. Colombo 81, 20133 Milan, ItalySchool of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKMolecular & Structural Biosciences, School of Life Sciences, Keele University, Huxley Building, Keele, Staffordshire ST5 5BG, UKTherapeutic options for Alzheimer’s disease, the most common form of dementia, are currently restricted to palliative treatments. The glycosaminoglycan heparin, widely used as a clinical anticoagulant, has previously been shown to inhibit the Alzheimer’s disease-relevant β-secretase 1 (BACE1). Despite this, the deployment of pharmaceutical heparin for the treatment of Alzheimer’s disease is largely precluded by its potent anticoagulant activity. Furthermore, ongoing concerns regarding the use of mammalian-sourced heparins, primarily due to prion diseases and religious beliefs hinder the deployment of alternative heparin-based therapeutics. A marine-derived, heparan sulphate-containing glycosaminoglycan extract, isolated from the crab <i>Portunus pelagicus</i>, was identified to inhibit human BACE1 with comparable bioactivity to that of mammalian heparin (IC<sub>50</sub> = 1.85 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.94) and 2.43 μg mL<sup>−1</sup> (R<sup>2</sup> = 0.93), respectively), while possessing highly attenuated anticoagulant activities. The results from several structural techniques suggest that the interactions between BACE1 and the extract from <i>P. pelagicus</i> are complex and distinct from those of heparin.https://www.mdpi.com/1660-3397/17/5/293Alzheimer’s diseaseamyloid-βBACE1β-secretaseglycosaminoglycanheparan sulphateheparin<i>Portunus pelagicus</i> |
| spellingShingle | Courtney J. Mycroft-West Lynsay C. Cooper Anthony J. Devlin Patricia Procter Scott E. Guimond Marco Guerrini David G. Fernig Marcelo A. Lima Edwin A. Yates Mark A. Skidmore A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease Marine Drugs Alzheimer’s disease amyloid-β BACE1 β-secretase glycosaminoglycan heparan sulphate heparin <i>Portunus pelagicus</i> |
| title | A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease |
| title_full | A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease |
| title_fullStr | A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease |
| title_full_unstemmed | A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease |
| title_short | A Glycosaminoglycan Extract from <i>Portunus pelagicus</i> Inhibits BACE1, the β Secretase Implicated in Alzheimer’s Disease |
| title_sort | glycosaminoglycan extract from i portunus pelagicus i inhibits bace1 the β secretase implicated in alzheimer s disease |
| topic | Alzheimer’s disease amyloid-β BACE1 β-secretase glycosaminoglycan heparan sulphate heparin <i>Portunus pelagicus</i> |
| url | https://www.mdpi.com/1660-3397/17/5/293 |
| work_keys_str_mv | AT courtneyjmycroftwest aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT lynsayccooper aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT anthonyjdevlin aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT patriciaprocter aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT scotteguimond aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT marcoguerrini aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT davidgfernig aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT marceloalima aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT edwinayates aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT markaskidmore aglycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT courtneyjmycroftwest glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT lynsayccooper glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT anthonyjdevlin glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT patriciaprocter glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT scotteguimond glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT marcoguerrini glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT davidgfernig glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT marceloalima glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT edwinayates glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease AT markaskidmore glycosaminoglycanextractfromiportunuspelagicusiinhibitsbace1thebsecretaseimplicatedinalzheimersdisease |