title: Pre-activated blood platelets and a pro-thrombotic phenotype in APP23 mice modeling Alzheimer's disease.
abstract: Platelet activation and thrombus formation play a critical role in primary hemostasis but also represent a pathophysiological mechanism leading to acute thrombotic vascular occlusions. Besides, platelets modulate cellular processes including inflammation, angiogenesis and neurodegeneration. On the other hand, platelet activation and thrombus formation are altered in different diseases leading to either bleeding complications or pathological thrombus formation. For many years platelets have been considered to play a role in neuroinflammatory diseases such as Alzheimer's disease (AD). AD is characterized by deposits of amyloid-β (Aβ) and strongly related to vascular diseases with platelets playing a critical role in the progression of AD because exposure of platelets to Aβ induces platelet activation, platelet Aβ release, and enhanced platelet adhesion to collagen in vitro and at the injured carotid artery in vivo. However, the molecular mechanisms and the relation between vascular pathology and amyloid-β plaque formation in the pathogenesis of AD are not fully understood. Compelling evidence is suggestive for altered platelet activity in AD patients. Thus we analyzed platelet activation and thrombus formation in aged AD transgenic mice (APP23) known to develop amyloid-β deposits in the brain parenchyma and cerebral vessels. As a result, platelets are in a pre-activated state in blood of APP23 mice and showed strongly enhanced integrin activation, degranulation and spreading kinetics on fibrinogen surfaces upon stimulation. This enhanced platelet signaling translated into almost unlimited thrombus formation on collagen under flow conditions in vitro and accelerated vessel occlusion in vivo suggesting that these mice are at high risk of arterial thrombosis leading to cerebrovascular and unexpectedly to cardiovascular complications that might be also relevant in AD patients.
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jarre
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Nina S
authors.initials: NS
authors.lastname: Gowert
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Lili
authors.initials: L
authors.lastname: Donner
authors.affiliation: Department of Physiology, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Münzer
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Klier
authors.affiliation: Department of Physiology, Eberhard-Karls University, Tübingen, Germany; Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard-Karls-Universität, Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: Department of Dermatology, University of Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schaller
authors.affiliation: Department of Physiology, Eberhard-Karls University, Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.affiliation: Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich-Heine-University, Düsseldorf, Germany. Electronic address: margitta.elvers@med.uni-duesseldorf.de.
authors.forename: Margitta
authors.initials: M
authors.lastname: Elvers
mesh_terms: D000544:Alzheimer Disease; D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D006023:Glycoproteins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D019007:P-Selectin / Q000378:metabolism; D010641:Phenotype; D015539:Platelet Activation; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology
chemical_list: D006023:Glycoproteins; D016023:Integrins; D019007:P-Selectin; D013917:Thrombin
keywords: Alzheimer's disease; Arterial thrombosis; Cerebral amyloid angiopathy; Hemostasis; Platelets