Fibrillar amyloid peptides promote platelet aggregation through the coordinated action of ITAM- and ROS-dependent pathways

Caterina Visconte, Jessica Canino, Mauro Vismara, Gianni Francesco Guidetti, Sara Raimondi, Giordano Pula, Mauro Torti, Ilaria Canobbio

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Amyloid peptides Aβ40 and Aβ42, whose deposition in brain correlates with Alzheimer disease, are also present in platelets and have prothrombotic activities. Objective: In this study, we analyze the ability of Aβ peptides to form fibrils and to induce platelet activation and aggregation. Methods: Aβ40, Aβ42, and their scrambled peptides were diluted in phosphate buffered saline and fibrillogenesis was investigated by ThioflavinT and Congo Red. Aggregation, protein phosphorylation, and reactive oxygen species (ROS) production were analyzed. Results: Aβ40 and Aβ42, but not scrambled peptides, were able to form fibrils when diluted in phosphate buffered saline. Fibrillogenesis of Aβ42 was very rapid, whereas fibril formation by Aβ40 was completed only after 48 hours of incubation. Fibrillar Aβ40 and Aβ42 promoted dose-dependent aggregation of washed platelets in the presence of extracellular CaCl2. Cleavage of GPIbα by mocarhagin or blockade of the ITAM-containing FcγRIIA prevented platelet aggregation induced by fibrillary Aβ40 and Aβ42. Fibrillar Aβ peptides stimulated the phosphorylation of FcγRIIA, resulting in the downstream stimulation of PLC, protein kinase C, and phosphoinositide 3-kinases, whose activity was necessary for full aggregation of platelets. Fibrillar Aβ peptides also induced ROS generation, and NOX inhibitors, as well as ROS scavengers, prevented platelet aggregation. However, Aβ peptide-induced ROS production did not require binding to GPIbα or activation of FcγRIIA, but was initiated by CD36, which provided an important contribution to full platelet aggregation. Conclusion: These results suggest that fibrillar amyloid Aβ40 and Aβ42 induce platelet aggregation through the recruitment of GPIb-IX-V and CD36, which requires the convergence of ITAM- and ROS-dependent pathways.

Original languageEnglish
Pages (from-to)3029-3042
Number of pages14
JournalJournal of Thrombosis and Haemostasis
Volume18
Issue number11
DOIs
Publication statusPublished - Nov 1 2020

Keywords

  • amyloid
  • blood platelets
  • platelet aggregation
  • protein-tyrosine kinases
  • reactive oxygen species

ASJC Scopus subject areas

  • Hematology

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