TY - JOUR
T1 - Fibrinogen and β-Amyloid Association Alters Thrombosis and Fibrinolysis
T2 - A Possible Contributing Factor to Alzheimer's Disease
AU - Cortes-Canteli, Marta
AU - Paul, Justin
AU - Norris, Erin H.
AU - Bronstein, Robert
AU - Ahn, Hyung Jin
AU - Zamolodchikov, Daria
AU - Bhuvanendran, Shivaprasad
AU - Fenz, Katherine M.
AU - Strickland, Sidney
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (NS50537 and GM66699), Institute for the Study of Aging (261104), Alzheimer's Drug Discovery Foundation (281203), Alzheimer's Association (IIRG-04-1356), Woodbourne Foundation, Blanchette Hooker Rockefeller Fund, May and Samuel Rudin Family Foundation, Bridges to Better Medicine Technology Fund, and NIH Medical Scientist Training Program (GM07739). M.C.-C. was supported by The Rockefeller University Women & Science Fellowship Program and by the American Health Assistance Foundation. We thank the Alzheimer's Disease Research Center at Washington University (P50 AG05681 grant) and the Harvard Brain Tissue Resource Center (PHS grant R24-MH 068855) for providing human samples, and the support of the two-photon Olympus microscope by the Empire State Stem Cell Fund through NYSDOH Contract #C023046. We thank Anita Ramnarain for assistance in mouse genotyping, Alexander Bounoutas, Maxime Kinet, Barry Coller, Marketa Jirouskova, and members of the Strickland laboratory for helpful discussions, and Alison J. North and Kunihiro Uryu at The Rockefeller University's Bio-Imaging and Electron Microscopy Resource Centers. We greatly appreciate assistance from Sarah Bhagat and the Bruce McEwen laboratory with behavioral experiments. We thank M. Azhar Chishti and David Westaway for the TgCRND8 mice, Genentech for recombinant tPA, the New York Blood Center for human plasma, and David E. Levy, Neurobiological Technologies, for ancrod.
PY - 2010/6
Y1 - 2010/6
N2 - Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.
AB - Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.
KW - Cellbio
KW - Humdisease
KW - Molneuro
UR - http://www.scopus.com/inward/record.url?scp=77953679700&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953679700&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2010.05.014
DO - 10.1016/j.neuron.2010.05.014
M3 - Article
C2 - 20547128
AN - SCOPUS:77953679700
SN - 0896-6273
VL - 66
SP - 695
EP - 709
JO - Neuron
JF - Neuron
IS - 5
ER -