| First Author | Donner L | Year | 2016 |
| Journal | Sci Signal | Volume | 9 |
| Issue | 429 | Pages | ra52 |
| PubMed ID | 27221710 | Mgi Jnum | J:258640 |
| Mgi Id | MGI:6142162 | Doi | 10.1126/scisignal.aaf6240 |
| Citation | Donner L, et al. (2016) Platelets contribute to amyloid-beta aggregation in cerebral vessels through integrin alphaIIbbeta3-induced outside-in signaling and clusterin release. Sci Signal 9(429):ra52 |
| abstractText | Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-beta (Abeta) in the walls of cerebral vessels. CAA and Abeta deposition in the brain parenchyma contribute to dementia and Alzheimer''s disease (AD). We investigated the contribution of platelets, which accumulate at vascular Abeta deposits, to CAA. We found that synthetic monomeric Abeta40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin alphaIIbbeta3, which is the receptor for the extracellular matrix protein fibrinogen, and stimulated the secretion of adenosine diphosphate (ADP) and the chaperone protein clusterin from platelets. Clusterin promoted the formation of fibrillar Abeta aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin alphaIIbbeta3 activation, further increasing the secretion of clusterin and Abeta40 binding to platelets. Platelets from patients with Glanzmann''s thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional alphaIIbbeta3, indicated that the abundance of this integrin dictated Abeta-induced clusterin release and platelet-induced Abeta aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Abeta aggregation in platelet cultures; in transgenic AD model mice, this drug reduced the amount of clusterin in the circulation and the incidence of CAA. Our findings indicate that activated platelets directly contribute to CAA by promoting the formation of Abeta aggregates and that Abeta, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients. |
