Amyloid Peptide β1-42 Induces Integrin αIIbβ3 Activation, Platelet Adhesion, and Thrombus Formation in a NADPH Oxidase-Dependent Manner

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 beta amyloid peptides on the function of platelets, the cells driving haemostasis. Amyloid peptide beta 1-42 (A beta 1-42), A beta 1-40, and A beta 25-35 were tested in static adhesion experiments, and it was found that platelets preferentially adhere to A beta 1-42 compared to other A beta peptides. In addition, significant platelet spreading was observed over A beta 1-42, while A beta 1-40, A beta 25-35, and the scA beta 1-42 control did not seem to induce any platelet spreading, which suggested that only A beta 1-42 activates platelet signalling in our experimental conditions. A beta 1-42 also induced significant platelet adhesion and thrombus formation in whole blood under venous flow condition, while other A beta peptides did not. The molecular mechanism of A beta 1-42 was investigated by flow cytometry, which revealed that this peptide induces a significant activation of integrin alpha IIb beta 3, but does not induce platelet degranulation (as measured by P-selectin membrane translocation). Finally, A beta 1-42 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 A beta 1-42-dependent platelet adhesion in static conditions, thrombus formation in physiological flow conditions, integrin alpha IIb beta 3 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 beta 1-42. The molecular mechanisms described in this manuscript may play an important role in the neurovascular impairment observed in Alzheimer's patients.