Abstract Number: PB1748
Meeting: ISTH 2020 Congress
Background: Abnormal deposition of amyloid peptides Aβ40 and Aβ42 in brain is correlated with the onset of Alzheimer’s Disease. Aβ40 and Aβ42 are also present in platelets and deposit in cerebral vessels. Aβ40 and Aβ42 promote platelet adhesion and activation and generate a pro-inflammatory state. The molecular mechanism of amyloid peptide-induced platelet activation is not clearly defined.
Aims: In this study we have investigated the signalling pathway triggered by fibrillar amyloid peptides to promote platelet aggregation and ROS formation.
Methods: Amyloid peptides Aβ40 and Aβ42, and their respective scrambled peptides, were dissolved in DMSO and then diluted in PBS for 48 hours. Fibril formation was evaluated by ThioflavinT and Congo Red staining. Aggregation of washed platelets was evaluated in parallel with the analysis of the activation of signalling effectors in immunoblotting. Generation of intracellular Reactive Oxygen Species (ROS) was analysed in flow cytometry.
Results: Aβ40 and Aβ42 dilution in PBS for 48 hours resulted in the formation of amyloid fibrils with β-sheet structure. Fibrillar Aβ40 and Aβ42, but not their scrambled peptides or the synthetic Aβ25-35 peptide, promoted platelet aggregation with comparable efficacy by interacting with GPIbα and triggering the activation of associated FcγRIIA. Stimulation of PLC, PKC and PI3K by fibrillary Aβ peptides was ITAM- and Src family kinase-dependent and was required for platelet aggregation. Fibrillar Aβ also induced Src family kinase-dependent 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 was also shown to be necessary for full platelet aggregation induced by fibrillar Aβ peptides.
Conclusions: Differently from soluble forms of amyloid peptides, fibrillary amyloid Aβ40 and Aβ42 induce platelet aggregation through the recruitment of GPIb-IX-V and CD36 and the convergence of ITAM- and ROS-dependent pathways.
To cite this abstract in AMA style:Visconte C, Canino J, Vismara M, Galgano L, Pula G, Guidetti G, Torti M, Canobbio I. Fibrillar Amyloid Peptides Promote Platelet Aggregation through the Coordinated Action of ITAM- and ROS-Dependent Pathways [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/fibrillar-amyloid-peptides-promote-platelet-aggregation-through-the-coordinated-action-of-itam-and-ros-dependent-pathways/. Accessed November 30, 2021.
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