期刊
NEUROBIOLOGY OF DISEASE
卷 31, 期 2, 页码 198-208出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2008.04.005
关键词
tau; nitration; Alzheimer's disease; astrocytes; monoclonal antibody; glial fibrillary acidic protein; tyrosine
资金
- NIA NIH HHS [AG09466, P01 AG021184-01A10002, P01 AG009466-14A1, AG021184, P01 AG021184] Funding Source: Medline
- NIGMS NIH HHS [R25 GM068929, R25-GM068929, R25 GM068929-04] Funding Source: Medline
Alzheimer's disease (AD) pathology has been characterized, in part, by the self-assembly of the tau molecule into neurofibrillary tangles (NFT). While different post-translational modifications have been identified that accelerate tau aggregation, nitration at tyrosine residues prevents or slows tau filament formation in vitro. Of the five tyrosine residues within the molecule, nitration at the first tyrosine residue (Tyr 18) results in a profound inhibition of filament self-assembly. To determine whether nitration at Tyr 18 occurs in AD pathology, monoclonal antibodies were raised against a synthetic tau peptide nitrated at Tyr 18. A clone, termed Tau-nY18, reacts specifically with tau proteins nitrated at Tyr 18 and fails to cross-react with other nitrated tyrosine residues spanning the length of the molecule or with other proteins known to be nitrated in neurodegenerative diseases. In situ, Tau-nY18 sparsely labels the neuronal pathological hallmarks of the disease, including NFT and dystrophic neurites. Surprisingly however, Tau-nY18 robustly labels nitrated tau within activated, GFAP positive astrocytes intimately associated with amyloid plaques. Furthermore, this antibody detects nitrated tau in soluble preparations from both severe AD brains (Braak stage V, VI) and age-matched controls. Collectively, these findings suggest that nitration at Tyr IS may be linked to astrocyte activation, an early event associated with amyloid plaque formation. (C) 2008 Elsevier Inc. All rights reserved.
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