A possible link between astrocyte activation and tau nitration in Alzheimer's disease.
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 18 may be linked to astrocyte activation, an early event associated with amyloid plaque formation.
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. juan-reyes@northwestern.edu
Juan F
JF
Reyes
Matthew R
MR
Reynolds
Peleg M
PM
Horowitz
Yifan
Y
Fu
Angela L
AL
Guillozet-Bongaarts
Robert
R
Berry
Lester I
LI
Binder
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D005904:Glial Fibrillary Acidic Protein; D009566:Nitrates; D016875:tau Proteins; D014443:Tyrosine