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

Lili Donner, Laura Mara Toska, Irena Krüger, Sandra Gröniger, Ruben Barroso, Alice Burleigh, Diego Mezzano, Susanne Pfeiler, Malte Kelm, Norbert Gerdes, Steve P Watson, Yi Sun, Margitta Elvers

Science signaling 2020 Aug 04

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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. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Lili Donner, Laura Mara Toska, Irena Krüger, Sandra Gröniger, Ruben Barroso, Alice Burleigh, Diego Mezzano, Susanne Pfeiler, Malte Kelm, Norbert Gerdes, Steve P Watson, Yi Sun, Margitta Elvers. The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid. Science signaling. 2020 Aug 04;13(643)