title: The Alzheimer's disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII.
abstract: Essentials How the Alzheimer's disease (AD) peptide β-amyloid (Aβ) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aβ triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aβ-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target.
  
  
  
  Background β-Amyloid (Aβ) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Aβ to contribute to a prothrombotic state. Methods and results We show that Aβ activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Aβ as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Aβ to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD.
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zamolodchikov
authors.affiliation: Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Renné
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000544:Alzheimer Disease / Q000097:blood*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry; D000818:Animals; D001777:Blood Coagulation; D001783:Blood Flow Velocity; D002560:Cerebrovascular Circulation; D050718:Complement C1 Inhibitor Protein / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005174:Factor XII / Q000737:chemistry*; D005260:Female; D005337:Fibrin / Q000737:chemistry; D064368:Healthy Volunteers; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D013917:Thrombin / Q000737:chemistry*; D013927:Thrombosis / Q000097:blood; D016896:Treatment Outcome
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D050718:Complement C1 Inhibitor Protein; D005174:Factor XII; D005337:Fibrin; D013917:Thrombin
keywords: Alzheimer's disease; amyloid β-peptides; factor XI; factor XII; thrombin