title: Platelets contribute to amyloid-β aggregation in cerebral vessels through integrin αIIbβ3-induced outside-in signaling and clusterin release.
abstract: 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.
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Lili
authors.initials: L
authors.lastname: Donner
authors.affiliation: Cardiovascular Research Centre, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Knut
authors.initials: K
authors.lastname: Fälker
authors.affiliation: Institute of Physical Biology, Heinrich Heine University, 40225 Düsseldorf, Germany. Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.affiliation: Institute of Physical Biology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klinker
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pagani
authors.affiliation: Cardiovascular Research Centre, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Liza U
authors.initials: LU
authors.lastname: Ljungberg
authors.affiliation: Institute of Physical Biology, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Lothmann
authors.affiliation: Department of Biomedical, Biotechnological, and Translation Sciences, University of Parma, Via Volturno 39/a, 43126 Parma, Italy. Centre for Molecular and Translational Oncology (COMT), University of Parma, Parco Area delle Scienze 11/a, 43124 Parma, Italy. National Institute of Biostructure and Biosystems (INBB), Viale Medaglie d'Oro 305, 00136 Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzi
authors.affiliation: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Department of Mathematics and Natural Sciences, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
authors.affiliation: Institute of Physical Biology, Heinrich Heine University, 40225 Düsseldorf, Germany. Institute of Structural Biochemistry (ICS-6), Research Centre Jülich, 52425 Jülich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Cardiovascular Research Centre, Örebro University, SE-701 82 Örebro, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Grenegard
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany. margitta.elvers@med.uni-duesseldorf.de.
authors.forename: Margitta
authors.initials: M
authors.lastname: Elvers
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation; D051152:Clusterin / Q000378:metabolism*; D003433:Crosses, Genetic; D018450:Disease Progression; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005838:Genotype; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; C056564:ITGA2B protein, human; D039421:Integrin alpha2; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005340:Fibrinogen