title: Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma.
abstract: Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065;
authors.forename: Daria
authors.initials: D
authors.lastname: Zamolodchikov
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065;
authors.forename: Zu-Lin
authors.initials: ZL
authors.lastname: Chen
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065;
authors.forename: Brooke A
authors.initials: BA
authors.lastname: Conti
authors.affiliation: Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, and Center of Molecular Medicine, Karolinska Institutet and University Hospital, SE-171 76 Stockholm, Sweden; and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065; strickland@rockefeller.edu.
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D015956:Factor XIIa / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation; D007610:Kallikreins / Q000097:blood; D007704:Kininogens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D010446:Peptide Fragments / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D007704:Kininogens; D010446:Peptide Fragments; D014168:Transferrin; C075222:amyloid beta-protein (1-42); D005174:Factor XII; D007610:Kallikreins; D015956:Factor XIIa
keywords: Alzheimer’s disease; factor XII; high molecular-weight kininogen; plasma kallikrein