Amyloid peptide β 1-42 induces integrin α IIb β 3 activation, platelet adhesion, and thrombus formation in a NADPH Oxidase-Dependent Manner

Aisha Alsheikh Abubaker, Dina Vara, Caterina Visconte, Ian Eggleston, Mauro Torti, Ilaria Canobbio, Giordano Pula

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number1050476
Pages (from-to)1-12
Number of pages12
JournalOxidative Medicine and Cellular Longevity
Volume2019
DOIs
Publication statusPublished - 14 Mar 2019

Keywords

  • Amyloid beta-Peptides/toxicity
  • Benzoxazoles/pharmacology
  • Humans
  • NADPH Oxidases/metabolism
  • Peptide Fragments/toxicity
  • Platelet Adhesiveness/drug effects
  • Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
  • Signal Transduction/drug effects
  • Thrombosis/pathology
  • Triazoles/pharmacology

ASJC Scopus subject areas

  • Ageing
  • Biochemistry
  • Cell Biology

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