title: Nitration of tau protein is linked to neurodegeneration in tauopathies.
abstract: Oxidative and nitrative injury is implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome (DS), but no direct evidence links this type of injury to the formation of neurofibrillary tau lesions. To address this, we generated a monoclonal antibody (mAb), n847, which recognizes nitrated tau and alpha-synuclein. n847 detected nitrated tau in the insoluble fraction of AD, corticobasal degeneration (CBD), and Pick's disease (PiD) brains by Western blots. Immunohistochemistry (IHC) showed that n847 labeled neurons in the hippocampus and neocortex of AD and DS brains. Double-label immunofluorescence with n847 and an anti-tau antibody revealed partial co-localization of tau and n847 positive tangles, while n847 immunofluorescence and Thioflavin-S double-staining showed that a subset of n847-labeled neurons were Thioflavin-S-positive. In addition, immuno-electron microscopy revealed that tau-positive filaments in tangle-bearing neurons were also labeled by n847 and IHC of other tauopathies showed that some of glial and neuronal tau pathologies in CBD, progressive supranuclear palsy, PiD, and frontotemporal dementia with parkinsonism linked to chromosome 17 also were n847-positive. Finally, nitrated and Thioflavin-S-positive tau aggregates were generated in a oligodendrocytic cell line after treatment with peroxynitrite. Taken together, these findings imply that nitrative injury is directly linked to the formation of filamentous tau inclusions.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Horiguchi
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
authors.forename: Richard
authors.initials: R
authors.lastname: LightFoot
authors.forename: Christine
authors.initials: C
authors.lastname: Bellmann
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Landsberg
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001479:Basal Ganglia; D052160:Benzothiazoles; D002460:Cell Line; D002540:Cerebral Cortex; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000209:etiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D020774:Pick Disease of the Brain / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000150:complications* / Q000378:metabolism*; D013844:Thiazoles; D014018:Tissue Distribution; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D005456:Fluorescent Dyes; D009566:Nitrates; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T