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

Cerebral amyloid angiopathy (CAA) and beta-amyloid (A beta) deposition in the brain parenchyma are hallmarks of Alzheimer's disease (AD). We previously reported that platelets contribute to A beta aggregation in cerebral vessels by secreting the factor clusterin upon binding of A beta 40 to the fibrinogen receptor integrin alpha(IIb)beta(3). 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 A beta 40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of A beta 40 to integrin alpha(IIb)beta(3), fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of alpha(IIb)beta(3) or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of A beta-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased A beta 40-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 AD beta 40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin alpha(IIb)beta(3) Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.