Amyloid peptide β1-42 induces integrin αIIbβ3 activation, platelet adhesion and thrombus formation in a NADPH oxidase-dependent manner
dc.contributor.author | Abubaker, A | |
dc.contributor.author | Vara, D | |
dc.contributor.author | Visconte, C | |
dc.contributor.author | Eggleston, I | |
dc.contributor.author | Torti, M | |
dc.contributor.author | Canobbio, I | |
dc.contributor.author | Pula, G | |
dc.date.accessioned | 2019-03-05T13:25:07Z | |
dc.date.issued | 2019-03-14 | |
dc.description.abstract | The progression of Alzheimer’s dementia is associated with neurovasculature impairment, which includes inflammation, microthromboses, and reduced cerebral blood flow. Here, we investigate the effects of β amyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptide β1-42 (Aβ1-42), Aβ1-40, and Aβ25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to Aβ1-42 compared to other Aβ peptides. In addition, significant platelet spreading was observed over Aβ1-42, while Aβ1-40, Aβ25-35, and the scAβ1-42 control did not seem to induce any platelet spreading, which suggested that only Aβ1-42 activates platelet signalling in our experimental conditions. Aβ1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aβ peptides did not. The molecular mechanism of Aβ1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrin αIIbβ3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, Aβ1-42 treatment of human platelets led to detectable levels of protein kinase C (PKC) activation and tyrosine phosphorylation, which are hallmarks of platelet signalling. Interestingly, the NADPH oxidase (NOX) inhibitor VAS2870 completely abolished Aβ1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrin αIIbβ3 activation, and tyrosine- and PKC-dependent platelet signalling. In summary, this study highlights the importance of NOXs in the activation of platelets in response to amyloid peptide β1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer’s patients. | en_GB |
dc.description.sponsorship | Alzheimer´s Research UK | en_GB |
dc.description.sponsorship | British Heart Foundation | en_GB |
dc.description.sponsorship | National Institute for Health Research (NIHR) | en_GB |
dc.identifier.citation | Vol. 2019, article 1050476 | en_GB |
dc.identifier.doi | 10.1155/2019/1050476 | |
dc.identifier.grantnumber | ARUK-PG2017A-3 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/36286 | |
dc.language.iso | en | en_GB |
dc.publisher | Hindawi Publishing Corporation | en_GB |
dc.rights | © 2019 Aisha Alsheikh Abubaker et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.title | Amyloid peptide β1-42 induces integrin αIIbβ3 activation, platelet adhesion and thrombus formation in a NADPH oxidase-dependent manner | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-03-05T13:25:07Z | |
dc.identifier.issn | 1942-0900 | |
dc.description | This is the final version. Available on open access from Hindawi Publishing Corporation via the DOI in this record | en_GB |
dc.identifier.journal | Oxidative Medicine and Cellular Longevity | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2018-12-13 | |
exeter.funder | ::Alzheimer´s Research UK | en_GB |
exeter.funder | ::British Heart Foundation | en_GB |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2018-12-13 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-03-05T12:44:05Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2019-03-21T14:32:23Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © 2019 Aisha Alsheikh Abubaker et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.