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Brain Advance Access originally published online on February 27, 2009
Brain 2009 132(5):1335-1345; doi:10.1093/brain/awp023
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation

Francesc X. Guix1,2, Gerard Ill-Raga1, Ramona Bravo3, Tadashi Nakaya4, Gianni de Fabritiis5, Mireia Coma1, Gian Pietro Miscione5, Jordi Villà-Freixa5, Toshiharu Suzuki4, Xavier Fernàndez-Busquets3, Miguel A. Valverde1, Bart de Strooper2,6 and Francisco J. Muñoz1

1 Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain 2 Department for Developmental and Molecular Genetics–VIB, Leuven, Belgium 3 Biomolecular Interactions Team, Institute for Bioengineering of Catalonia, and Nanoscience and Nanotechnology Institute, University of Barcelona, Spain 4 Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan 5 Unitat de Recerca en Informàtica Biomèdica, UPF-Institut Municipal d’Investigació Mèdica, Barcelona, Spain 6 Center for Human Genetics, Leuven, Belgium

Correspondence to: Dr Francisco J. Muñoz, Grup de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, C/ Dr Aiguader, 88, 08003 Barcelona, Spain E-mail: paco.munoz{at}upf.edu

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.

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

Abbreviations: AFM, Atomic Force Microscopy; DHAP, dihydroxyacetone phosphate; GAP, D-glyceraldehyde 3-phosphate; NFT, neurofibrillary tangles; PHF, paired helical filaments; PS1, presenilin 1; SIN-1, peroxynitrite donor; TEM, Transmission electron microscopy; TPI, triosephosphate isomerase

Received August 6, 2008. Revised January 11, 2009. Accepted January 15, 2009.


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