The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid

Cerebral amyloid angiopathy (CAA) and β-amyloid (Aβ) deposition in the brain parenchyma are hallmarks of Alzheimer's disease (AD). We previously reported that platelets contribute to Aβ aggregation in cerebral vessels by secreting the factor clusterin upon binding of Aβ40 to the fibrinogen receptor integrin α_IIbβ₃ 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 Aβ40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of Aβ40 to integrin α_IIbβ₃, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of α_IIbβ₃ or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of Aβ-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased Aβ40-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 Aβ40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin α_IIbβ₃ Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.