| First Author | Donner L | Year | 2020 |
| Journal | Sci Signal | Volume | 13 |
| Issue | 643 | PubMed ID | 32753479 |
| Mgi Jnum | J:330073 | Mgi Id | MGI:6751920 |
| Doi | 10.1126/scisignal.aba9872 | Citation | Donner L, et al. (2020) The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of beta-amyloid. Sci Signal 13(643) |
| abstractText | Cerebral amyloid angiopathy (CAA) and beta-amyloid (Abeta) deposition in the brain parenchyma are hallmarks of Alzheimer's disease (AD). We previously reported that platelets contribute to Abeta aggregation in cerebral vessels by secreting the factor clusterin upon binding of Abeta40 to the fibrinogen receptor integrin alphaIIbbeta3 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 Abeta40 bound to GPVI, which induced the release of ATP and fibrinogen, resulting in platelet aggregation. Binding of Abeta40 to integrin alphaIIbbeta3, fibrinogen, and GPVI collectively contributed to the formation of amyloid clusters at the platelet surface. Consequently, blockade of alphaIIbbeta3 or genetic loss of GPVI reduced amyloid fibril formation in cultured platelets and decreased the adhesion of Abeta-activated platelets to injured carotid arteries in mice. Application of losartan to inhibit collagen binding to GPVI resulted in decreased Abeta40-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 Abeta40 promotes platelet-mediated amyloid aggregation by binding to both GPVI and integrin alphaIIbbeta3 Blocking these pathways may therapeutically reduce amyloid plaque formation in cerebral vessels and the brain parenchyma of patients. |
