Journal Article

Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation

Francesc X. Guix, Gerard Ill-Raga, Ramona Bravo, Tadashi Nakaya, Gianni de Fabritiis, Mireia Coma, Gian Pietro Miscione, Jordi Villà-Freixa, Toshiharu Suzuki, Xavier Fernàndez-Busquets, Miguel A. Valverde, Bart de Strooper and Francisco J. Muñoz

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 5, pages 1335-1345
Published in print May 2009 | ISSN: 0006-8950
Published online February 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp023
Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation

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Alzheimer's disease neuropathology is characterized by neuronal death, amyloid β-peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimer's disease, the molecular mechanisms linking amyloid β-peptide and paired helical filaments remain unknown. Here, we show that amyloid β-peptide-induced nitro-oxidative damage promotes the nitrotyrosination of the glycolytic enzyme triosephosphate isomerase in human neuroblastoma cells. Consequently, nitro-triosephosphate isomerase was found to be present in brain slides from double transgenic mice overexpressing human amyloid precursor protein and presenilin 1, and in Alzheimer's disease patients. Higher levels of nitro-triosephosphate isomerase (P < 0.05) were detected, by Western blot, in immunoprecipitates from hippocampus (9 individuals) and frontal cortex (13 individuals) of Alzheimer's disease patients, compared with healthy subjects (4 and 9 individuals, respectively). Triosephosphate isomerase nitrotyrosination decreases the glycolytic flow. Moreover, during its isomerase activity, it triggers the production of the highly neurotoxic methylglyoxal (n = 4; P < 0.05). The bioinformatics simulation of the nitration of tyrosines 164 and 208, close to the catalytic centre, fits with a reduced isomerase activity. Human embryonic kidney (HEK) cells overexpressing double mutant triosephosphate isomerase (Tyr164 and 208 by Phe164 and 208) showed high methylglyoxal production. This finding correlates with the widespread glycation immunostaining in Alzheimer's disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large β-sheet aggregates in vitro and in vivo, as demonstrated by turbidometric analysis and electron microscopy. Transmission electron microscopy (TEM) and atomic force microscopy studies have demonstrated that nitro-triosephosphate isomerase binds tau monomers and induces tau aggregation to form paired helical filaments, the characteristic intracellular hallmark of Alzheimer's disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimer's disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid β-peptide-induced toxicity and tau pathology.

Keywords: Alzheimer's disease; amyloid β-peptide; tau protein; triosephosphate isomerase; peroxynitrite

Journal Article.  6758 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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