title: Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice.
abstract: Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII) -initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY; and.
authors.forename: Zu-Lin
authors.initials: ZL
authors.lastname: Chen
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY; and.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY; and.
authors.forename: Erin H
authors.initials: EH
authors.lastname: Norris
authors.affiliation: Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY; and.
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D060825:Cognitive Dysfunction / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005174:Factor XII / Q000378:metabolism*; D019679:Kininogen, High-Molecular-Weight / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D014652:Vascular Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D019679:Kininogen, High-Molecular-Weight; D005174:Factor XII