title: Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation.
abstract: 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.
authors: Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors: Markus P
authors: MP
authors: Kummer
authors: Michael
authors: M
authors: Hermes
authors: Andrea
authors: A
authors: Delekarte
authors: Thea
authors: T
authors: Hammerschmidt
authors: Sathish
authors: S
authors: Kumar
authors: Dick
authors: D
authors: Terwel
authors: Jochen
authors: J
authors: Walter
authors: Hans-Christian
authors: HC
authors: Pape
authors: Simone
authors: S
authors: König
authors: Sigrun
authors: S
authors: Roeber
authors: Frank
authors: F
authors: Jessen
authors: Thomas
authors: T
authors: Klockgether
authors: Martin
authors: M
authors: Korte
authors: Michael T
authors: MT
authors: Heneka
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001703:Biophysics; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004338:Drug Combinations; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse