title: Fibrinogen and altered hemostasis in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links Aβ with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with Aβ in the brain parenchyma and cerebral blood vessels. We found that Aβ and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, Aβ fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from Aβ-fibrin(ogen) binding and altered hemostasis and could thus contribute to Aβ deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and Aβ may be a promising therapeutic target for AD.
authors.affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Cortes-Canteli
authors.forename: Daria
authors.initials: D
authors.lastname: Zamolodchikov
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Ahn
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
authors.forename: Erin H
authors.initials: EH
authors.lastname: Norris
mesh_terms: D000544:Alzheimer Disease / Q000097:blood* / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005340:Fibrinogen / Q000378:metabolism*; D006487:Hemostasis / Q000502:physiology*; D006801:Humans
chemical_list: D005340:Fibrinogen