title: Amyloid β-peptide-dependent activation of human platelets: essential role for Ca2+ and ADP in aggregation and thrombus formation.
abstract: Alzheimer's disease is associated with the accumulation of Aβ (amyloid β)-peptides in the brain. Besides their cytotoxic effect on neurons, Aβ-peptides are thought to be responsible for the atherothrombotic complications associated with Alzheimer's disease, which are collectively known as cerebrovascular disease. In the present study, we investigated the effect of Aβ-peptides on human platelet signal transduction and function. We discovered that the 25-35 domain of Aβ-peptides induce an increase in platelet intracellular Ca2+ that stimulates α-granule and dense granule secretion and leads to the release of the secondary agonist ADP. Released ADP acts in an autocrine manner as a stimulant for critical signalling pathways leading to the activation of platelets. This includes the activation of the protein kinases Syk, protein kinase C, Akt and mitogen-activated protein kinases. Ca2+-dependent release of ADP is also the main component of the activation of the small GTPase Rap1b and the fibrinogen receptor integrin αIIbβ3, which leads to increased platelet aggregation and increased thrombus formation in human whole blood. Our discoveries complement existing understanding of cerebrovascular dementia and suggest that Aβ-peptides can induce vascular complications of Alzheimer's disease by stimulating platelets in an intracellular Ca2+-dependent manner. Despite a marginal ADP-independent component suggested by low levels of signalling activity in the presence of apyrase or P2Y receptor inhibitors, Ca2+-dependent release of ADP by Aβ-peptides clearly plays a critical role in platelet activation. Targeting ADP signalling may therefore represent an important strategy to manage the cerebrovascular component of Alzheimer's disease.
authors.affiliation: *Department of Biology and Biotechnology, Unit of Biochemistry, University of Pavia, Pavia 27100, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Canobbio
authors.affiliation: *Department of Biology and Biotechnology, Unit of Biochemistry, University of Pavia, Pavia 27100, Italy.
authors.forename: Gianni F
authors.initials: GF
authors.lastname: Guidetti
authors.affiliation: †Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia 27100, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Oliviero
authors.affiliation: *Department of Biology and Biotechnology, Unit of Biochemistry, University of Pavia, Pavia 27100, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Manganaro
authors.affiliation: ‡Department of Pharmacy and Pharmacology, Centre for Regenerative Medicine, University of Bath, Bath BA2 7AY, U.K.
authors.forename: Dina
authors.initials: D
authors.lastname: Vara
authors.affiliation: *Department of Biology and Biotechnology, Unit of Biochemistry, University of Pavia, Pavia 27100, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Torti
authors.affiliation: ‡Department of Pharmacy and Pharmacology, Centre for Regenerative Medicine, University of Bath, Bath BA2 7AY, U.K.
authors.forename: Giordano
authors.initials: G
authors.lastname: Pula
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000502:physiology; D015539:Platelet Activation; D010974:Platelet Aggregation / Q000187:drug effects; D015398:Signal Transduction
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D000244:Adenosine Diphosphate; D002118:Calcium