[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 :
Neurology
Author, co-author :
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.
Alderton W.K., Cooper C.E., Knowles R.G. Nitric oxide synthases: structure, function and inhibition. Biochem. J. 2001, 357:593-615.
Beal M.F. Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci. 2000, 23:298-304.
Butterfield D.A., Reed T.T., Perluigi M., De Marco C., Coccia R., Keller J.N., Markesbery W.R., Sultana R. Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res. 2007, 1148:243-248.
Castegna A., Thongboonkerd V., Klein J.B., Lynn B., Markesbery W.R., Butterfield D.A. Proteomic identification of nitrated proteins in Alzheimer's disease brain. J. Neurochem. 2003, 85:1394-1401.
Chen G., Kolbeck R., Barde Y.A., Bonhoeffer T., Kossel A. Relative contribution of endogenous neurotrophins in hippocampal long-term potentiation. J. Neurosci. 1999, 19:7983-7990.
Colton C.A., Vitek M.P., Wink D.A., Xu Q., Cantillana V., Previti M.L., Van Nostrand W.E., Weinberg J.B., Dawson H., Dawson H. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 2006, 103:12867-12872.
Colton C.A., Wilcock D.M., Wink D.A., Davis J., Van Nostrand W.E., Vitek M.P. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J. Alzheimers Dis. 2008, 15:571-587.
Combs C.K., Karlo J.C., Kao S.C., Landreth G.E. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 2001, 21:1179-1188.
Eisele Y.S., Bolmont T., Heikenwalder M., Langer F., Jacobson L.H., Yan Z.-X., Roth K., Aguzzi A., Staufenbiel M., Walker L.C., Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc. Natl. Acad. Sci. USA 2009, 106:12926-12931.
Ferger B., Themann C., Rose S., Halliwell B., Jenner P. 6-hydroxydopamine increases the hydroxylation and nitration of phenylalanine in vivo: implication of peroxynitrite formation. J. Neurochem. 2001, 78:509-514.
Fernández-Vizarra P., Fernández A.P., Castro-Blanco S., Encinas J.M., Serrano J., Bentura M.L., Muñoz P., Martínez-Murillo R., Rodrigo J. Expression of nitric oxide system in clinically evaluated cases of Alzheimer's disease. Neurobiol. Dis. 2004, 15:287-305.
Giasson B.I., Duda J.E., Murray I.V., Chen Q., Souza J.M., Hurtig H.I., Ischiropoulos H., Trojanowski J.Q., Lee V.M. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000, 290:985-989.
Glass C.K., Saijo K., Winner B., Marchetto M.C., Gage F.H. Mechanisms underlying inflammation in neurodegeneration. Cell 2010, 140:918-934.
Gow A.J., Farkouh C.R., Munson D.A., Posencheg M.A., Ischiropoulos H. Biological significance of nitric oxide-mediated protein modifications. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 287:L262-L268.
Griffin R., Nally R., Nolan Y., McCartney Y., Linden J., Lynch M.A. The age-related attenuation in long-term potentiation is associated with microglial activation. J. Neurochem. 2006, 99:1263-1272.
Hansel T.T., Kharitonov S.A., Donnelly L.E., Erin E.M., Currie M.G., Moore W.M., Manning P.T., Recker D.P., Barnes P.J. A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics. FASEB J. 2003, 17:1298-1300.
Hauss-Wegrzyniak B., Lynch M.A., Vraniak P.D., Wenk G.L. Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp. Neurol. 2002, 176:336-341.
He W., Barrow C.J. The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta. Biochemistry 1999, 38:10871-10877.
Heneka M.T., Wiesinger H., Dumitrescu-Ozimek L., Riederer P., Feinstein D.L., Klockgether T. Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2001, 60:906-916.
Hensley K., Maidt M.L., Yu Z., Sang H., Markesbery W.R., Floyd R.A. Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J. Neurosci. 1998, 18:8126-8132.
Horiguchi T., Uryu K., Giasson B.I., Ischiropoulos H., LightFoot R., Bellmann C., Richter-Landsberg C., Lee V.M., Trojanowski J.Q. Nitration of tau protein is linked to neurodegeneration in tauopathies. Am. J. Pathol. 2003, 163:1021-1031.
Inestrosa N.C., Reyes A.E., Chacón M.A., Cerpa W., Villalón A., Montiel J., Merabachvili G., Aldunate R., Bozinovic F., Aboitiz F. Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu. Neurobiol. Aging 2005, 26:1023-1028.
Ishii K., Muelhauser F., Liebl U., Picard M., Kühl S., Penke B., Bayer T., Wiessler M., Hennerici M., Beyreuther K., et al. Subacute NO generation induced by Alzheimer's beta-amyloid in the living brain: reversal by inhibition of the inducible NO synthase. FASEB J. 2000, 14:1485-1489.
Jäger S., Leuchtenberger S., Martin A., Czirr E., Wesselowski J., Dieckmann M., Waldron E., Korth C., Koo E.H., Heneka M., et al. alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Abeta generation. J. Neurochem. 2009, 111:1369-1382.
Jankowsky J.L., Slunt H.H., Ratovitski T., Jenkins N.A., Copeland N.G., Borchelt D.R. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol. Eng. 2001, 17:157-165.
Jankowsky J.L., Younkin L.H., Gonzales V., Fadale D.J., Slunt H.H., Lester H.A., Younkin S.G., Borchelt D.R. Rodent A beta modulates the solubility and distribution of amyloid deposits in transgenic mice. J. Biol. Chem. 2007, 282:22707-22720.
Jardanhazi-Kurutz D., Kummer M.P., Terwel D., Vogel K., Dyrks T., Thiele A., Heneka M.T. Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits. Neurochem. Int. 2010, 57:375-382.
Kato Y., Wu X., Naito M., Nomura H., Kitamoto N., Osawa T. Immunochemical detection of protein dityrosine in atherosclerotic lesion of apo-E-deficient mice using a novel monoclonal antibody. Biochem. Biophys. Res. Commun. 2000, 275:11-15.
Kretzschmar H.A., Prusiner S.B., Stowring L.E., DeArmond S.J. Scrapie prion proteins are synthesized in neurons. Am. J. Pathol. 1986, 122:1-5.
Laubach V.E., Shesely E.G., Smithies O., Sherman P.A. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc. Natl. Acad. Sci. USA 1995, 92:10688-10692.
Lee J., Chan S.L., Mattson M.P. Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain. Neuromolecular Med. 2002, 2:29-45.
LeVine H. Quantification of beta-sheet amyloid fibril structures with thioflavin T. Methods Enzymol. 1999, 309:274-284.
Lüth H.-J., Münch G., Arendt T. Aberrant expression of NOS isoforms in Alzheimer's disease is structurally related to nitrotyrosine formation. Brain Res. 2002, 953:135-143.
Meda L., Cassatella M.A., Szendrei G.I., Otvos L., Baron P., Villalba M., Ferrari D., Rossi F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995, 374:647-650.
Meyer-Luehmann M., Coomaraswamy J., Bolmont T., Kaeser S., Schaefer C., Kilger E., Neuenschwander A., Abramowski D., Frey P., Jaton A.L., et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 2006, 313:1781-1784.
Moore W.M., Webber R.K., Jerome G.M., Tjoeng F.S., Misko T.P., Currie M.G. L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J. Med. Chem. 1994, 37:3886-3888.
Nakamura T., Lipton S.A. Cell death: protein misfolding and neurodegenerative diseases. Apoptosis 2009, 14:455-468.
Nathan C., Calingasan N., Nezezon J., Ding A., Lucia M.S., La Perle K., Fuortes M., Lin M., Ehrt S., Kwon N.S., et al. Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J. Exp. Med. 2005, 202:1163-1169.
Olton D.S. The radial arm maze as a tool in behavioral pharmacology. Physiol. Behav. 1987, 40:793-797.
Petersson A.S., Steen H., Kalume D.E., Caidahl K., Roepstorff P. Investigation of tyrosine nitration in proteins by mass spectrometry. J. Mass Spectrom. 2001, 36:616-625.
Poderoso J.J. The formation of peroxynitrite in the applied physiology of mitochondrial nitric oxide. Arch. Biochem. Biophys. 2009, 484:214-220.
Querfurth H.W., LaFerla F.M. Alzheimer's disease. N. Engl. J. Med. 2010, 362:329-344.
Radi R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc. Natl. Acad. Sci. USA 2004, 101:4003-4008.
Rebello, S., Zhu, B., McMonagle-Strucko, K., and Pulicicchio, J. (2002). Pharmacokinetic and pharmacodynamic evaluation of inhibitors of inducible NitricOxide Synthase (iNOS) in mice. AAPS PharmSci. 4 (Suppl 1). http://www.aapsj.org/abstracts/AM_2002/AAPS2002-002237.pdf.
Rodrigo J., Fernández-Vizarra P., Castro-Blanco S., Bentura M.L., Nieto M., Gómez-Isla T., Martínez-Murillo R., MartInez A., Serrano J., Fernández A.P. Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice. Neuroscience 2004, 128:73-89.
Shivers B.D., Hilbich C., Multhaup G., Salbaum M., Beyreuther K., Seeburg P.H. Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact. EMBO J. 1988, 7:1365-1370.
Smith M.A., Richey Harris P.L., Sayre L.M., Beckman J.S., Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J. Neurosci. 1997, 17:2653-2657.
Souza J.M., Giasson B.I., Chen Q., Lee V.M., Ischiropoulos H. Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 2000, 275:18344-18349.
Szabó C., Ischiropoulos H., Radi R. Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat. Rev. Drug Discov. 2007, 6:662-680.
Tancredi V., D'Arcangelo G., Grassi F., Tarroni P., Palmieri G., Santoni A., Eusebi F. Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci. Lett. 1992, 146:176-178.
Tancredi V., D'Antuono M., Cafè C., Giovedì S., Buè M.C., D'Arcangelo G., Onofri F., Benfenati F. The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. J. Neurochem. 2000, 75:634-643.
Teplow D.B. Preparation of amyloid beta-protein for structural and functional studies. Methods Enzymol. 2006, 413:20-33.
Tran M.H., Yamada K., Olariu A., Mizuno M., Ren X.H., Nabeshima T. Amyloid beta-peptide induces nitric oxide production in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide synthase inhibitors. FASEB J. 2001, 15:1407-1409.
Vodovotz Y., Lucia M.S., Flanders K.C., Chesler L., Xie Q.W., Smith T.W., Weidner J., Mumford R., Webber R., Nathan C., et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. J. Exp. Med. 1996, 184:1425-1433.
Wahle T., Thal D.R., Sastre M., Rentmeister A., Bogdanovic N., Famulok M., Heneka M.T., Walter J. GGA1 is expressed in the human brain and affects the generation of amyloid beta-peptide. J. Neurosci. 2006, 26:12838-12846.
Wang Q., Rowan M.J., Anwyl R. Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J. Neurosci. 2004, 24:6049-6056.
Wilcock D.M., Lewis M.R., Van Nostrand W.E., Davis J., Previti M.L., Gharkholonarehe N., Vitek M.P., Colton C.A. Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J. Neurosci. 2008, 28:1537-1545.
