Amyloid Peptide ß1-42 Induces Integrin αIIbß3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner.

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 ß amyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptide ß1-42 (Aß1-42), Aß1-40, and Aß25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to Aß1-42 compared to other Aß peptides. In addition, significant platelet spreading was observed over Aß1-42, while Aß1-40, Aß25-35, and the scAß1-42 control did not seem to induce any platelet spreading, which suggested that only Aß1-42 activates platelet signalling in our experimental conditions. Aß1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other Aß peptides did not. The molecular mechanism of Aß1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrin αIIbß3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, Aß1-42 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 Aß1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrin αIIbß3 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 ß1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer's patients.