ABSTRACT
Cerebral amyloid angiopathy (CAA) and ß-amyloid (Aß) deposition in the brain parenchyma are hallmarks of Alzheimer's disease (AD). We previously reported that platelets contribute to Aß aggregation in cerebral vessels by secreting the factor clusterin upon binding of Aß40 to the fibrinogen receptor integrin αIIbß3 Here, we investigated the contribution of the collagen receptor GPVI (glycoprotein VI) in platelet-induced amyloid aggregation. Using platelets isolated from GPVI-wild type and GPVI-deficient human donors and mice, we found that Aß40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of Aß40 to integrin αIIbß3, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of αIIbß3 or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of Aß-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased Aß40-stimulated platelet activation, factor secretion, and platelet aggregation. Furthermore, the application of GPVI- or integrin-blocking antibodies reduced the formation of platelet-associated amyloid aggregates. Our findings indicate that Aß40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin αIIbß3 Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.
