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

Multiple receptors on platelets drive Alzheimer’s disease–associated amyloid deposits in brain vessels. Unclogging amyloid from arteries Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer’s disease in which the deposition of amyloid in vessels in the brain impairs blood flow. Amyloid can activate platelets, which promotes amyloid aggregation. Using platelets from patients and mice, Donner et al. found that blocking the collagen receptor GPVI may reduce CAA. Amyloid bound to GPVI on platelets and stimulated the release of fibrinogen that both clustered with soluble amyloid and bound a platelet-surface integrin that further promoted amyloid aggregation. Blockade of GPVI or the integrin reduced amyloid aggregation in platelet cultures, and loss of GPVI reduced the adhesion of amyloid-activated platelets in arteries in mice, revealing a potential therapeutic target to ameliorate CAA in patients. 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 αIIbβ3. 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 αIIbβ3, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of αIIbβ3 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 αIIbβ3. Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients.