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Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release
Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
Örebro University, School of Medical Sciences. Cardiovascular Research Centre, Örebro University Hospital, Örebro, Sweden.ORCID iD: 0000-0003-2519-203X
Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany; Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, Jülich, Germany.
Institute of Physical Biology, Heinrich Heine University, Düsseldorf, Germany.
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2016 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 429, article id ra52Article in journal (Refereed) Published
Abstract [en]

Cerebral amyloid angiopathy (CAA) is a vascular dysfunction disorder characterized by deposits of amyloid-β (Aβ) in the walls of cerebral vessels. CAA and Aβ deposition in the brain parenchyma contribute to dementia and Alzheimer's disease (AD). We investigated the contribution of platelets, which accumulate at vascular Aβ deposits, to CAA. We found that synthetic monomeric Aβ40 bound through its RHDS (Arg-His-Asp-Ser) sequence to integrin αIIbβ3, 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 Aβ aggregates, and ADP acted through its receptors P2Y1 and P2Y12 on platelets to enhance integrin αIIbβ3 activation, further increasing the secretion of clusterin and Aβ40 binding to platelets. Platelets from patients with Glanzmann's thrombasthenia, a bleeding disorder in which platelets have little or dysfunctional αIIbβ3, indicated that the abundance of this integrin dictated Aβ-induced clusterin release and platelet-induced Aβ aggregation. The antiplatelet agent clopidogrel, which irreversibly inhibits P2Y12, inhibited Aβ 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 Aβ aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop. Thus, antiplatelet therapy may alleviate fibril formation in cerebral vessels of AD patients.

Place, publisher, year, edition, pages
Washington, USA: American Association for the Advancement of Science (A A A S) , 2016. Vol. 9, no 429, article id ra52
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Cell Biology
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Cell Research
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URN: urn:nbn:se:oru:diva-50493DOI: 10.1126/scisignal.aaf6240ISI: 000376467800003PubMedID: 27221710Scopus ID: 2-s2.0-84971265417OAI: oai:DiVA.org:oru-50493DiVA, id: diva2:931990
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Funding Agency:

Julich Supercomputing Center HDD11

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2019-03-26Bibliographically approved

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Fälker, KnutLjungberg, Liza U.Grenegård, Magnus

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