Alzheimer's disease (AD) patients are closely associated with vascular pathology, and brain microvascular damage has been shown to occur years before the detection of amyloid and tau pathology. Prothrombin and thrombin were increased in the blood vessel walls of AD patients, and abnormal platelet activation status was found. Platelets play an important role in hemostasis, but they can also lead to pathological thrombosis. Recent studies have suggested that platelet activation may be a risk factor for vascular pathology in AD. However, whether platelet-mediated AD pathogenesis is associated with the risk of developing Alzheimer disease is unknown. We hypothesized that the platelet hyperactivity observed in AD patients could be linked to an amplified platelet response to thrombin in the presence of high levels of Aβ1-40. Through platelet adhesion and aggregation experiments, we demonstrated that thrombin-induced platelet adhesion and aggregation were indeed enhanced by Aβ1-40. Immunofluorescence confocal microscopy and fluorescence-activated cell sorting (FACS) analysis were employed to elucidate the underlying mechanisms. Our results confirmed that Aβ1-40 amplifies thrombin-induced platelet adhesion and aggregation, accompanied by an increase in integrin αIIbβ3 expression. Furthermore, we found that reactive oxygen species (ROS), specifically O2- and H2O2, involved in integrin αIIbβ3 signaling were amplified by Aβ1-40 in thrombin-induced platelets. The use of integrin αIIbβ3 inhibitors, antioxidants, and NADPH oxidase (NOX) inhibitors significantly reduced Aβ1-40-enhanced platelet activation and ROS generation. These findings suggest that the abnormal platelet activation observed in AD patients, where Aβ is present at high concentrations, may be driven by these mechanisms. Consequently, targeting integrin αIIbβ3 and NOX in platelets could present potential therapeutic strategies for addressing AD-associated vascular pathology.
