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Title: Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation
Authors: Guix, Francesc
Ill-Raga, Gerard
Bravo, Ramona
Nakaya, Tadashi
de Fabritiis, Gianni
Coma, Mireia
Pietro Miscione, Gian
Villa-Freixa, Jordi
Suzuki, Toshiharu
Fernandez-Busquets, Xavier
Valverde, Miguel A
De Strooper, Bart
Munoz, Francisco J # ×
Issue Date: May-2009
Publisher: Macmillan
Series Title: Brain vol:132 pages:1335-1345
Abstract: Alzheimers disease neuropathology is characterized by neuronal death, amyloid -peptide deposits and neurofibrillary tangles composed of paired helical filaments of tau protein. Although crucial for our understanding of the pathogenesis of Alzheimers disease, the molecular mechanisms linking amyloid -peptide and paired helical filaments remain unknown. Here, we show that amyloid -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 Alzheimers 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 Alzheimers 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 Alzheimers disease cortex and hippocampus from double transgenic mice overexpressing amyloid precursor protein and presenilin 1. Furthermore, nitro-triosephosphate isomerase formed large -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 Alzheimers disease brains. Our results link oxidative stress, the main etiopathogenic mechanism in sporadic Alzheimers disease, via the production of peroxynitrite and nitrotyrosination of triosephosphate isomerase, to amyloid -peptide-induced toxicity and tau pathology.
ISSN: 0006-8950
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

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