[en] Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid β (Aβ) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aβ). Nitration of Aβ accelerated its aggregation and was detected in the core of Aβ plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-Aβ, overall Aβ deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-Aβ into the brain of young APP/PS1 mice induced β-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.
Disciplines :
Neurologie
Auteur, co-auteur :
Kummer, Markus P; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Hermes, Michael; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Delekarte, Andrea; Division of Cellular Neurobiology, Zoological Institute, 38106 Braunschweig, Germany
Hammerschmidt, Thea; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany ; Institut for Physiology I, University of Münster, 48149 Münster, Germany
Kumar, Sathish; Molecular Neurology Group, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Terwel, Dick; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Walter, Jochen; Molecular Neurology Group, Department of Neurology, University of Bonn, 53127 Bonn, Germany
Pape, Hans-Christian; Institut for Physiology I, University of Münster, 48149 Münster, Germany
König, Simone; Integrated Functional Genomics, Interdisciplinary Center for Clinical Research Münster, 48149 Münster, Germany
Roeber, Sigrun; Institute for Neuropathology, Ludwig-Maximilian University, 81377 München, Germany
Jessen, Frank; Department of Psychiatry, University of Bonn, 53127 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
Klockgether, Thomas; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
Korte, Martin; Division of Cellular Neurobiology, Zoological Institute, 38106 Braunschweig, Germany
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, 53127 Bonn, Germany ; German Center for Neurodegenerative Diseases, 53175 Bonn, Germany
We thank Drs. Mathias Jucker and Gary Landreth for critically reading the manuscript. We are grateful to Drs. Sascha Weggen and Claus Pietrzik for providing antibody IC16, Dr. Yoji Kato for providing antibody IC3, and to Claudia Hülsmann, Daisy Axt, Ana Viera-Saecker, and Anna-Maria Mehlich for excellent technical assistance. The E7 antibody developed by M. Klymkowsky was obtained from the Developmental Studies Hybridoma Bank. This study was supported by the Deutsche Forschungsgemeinschaft (HE 3350/4-1 und HE 3350 4-2; KFO177, TP4) to M.T.H. M.P.K. and M.T.H. conceived the experiments. M.P.K., M.H., M.T.H., A.D., T.H., S. Kumar, and S. König carried out experiments. M.P.K., M.H., A.D., S. Kumar, S. König, M.K., and M.T.H. designed and carried out data analysis. S.R. and F.J. provided and characterized human samples. M.P.K., S. Kumar, S. König, D.T., J.W., T.K., M.K., and M.T.H. cowrote the paper. All authors participated in the discussion.
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