Methylglyoxal Produced by Amyloid-β Peptide-Induced Nitrotyrosination of Triosephosphate Isomerase Triggers Neuronal Death in Alzheimer’s Disease

Marta Tajes, Abel Eraso-Pichot, Fanny Rubio-Moscardó, Biuse Guivernau, Eva Ramos-Fernández, Mònica Bosch-Morató, Francesc Xavier Guix, Jordi Clarimón, Gian Pietro Miscione, Mercé Boada, Gabriel Gil-Gómez, Toshiharu Suzuki, Henrik Molina, Jordi Villà-Freixa, Rubén Vicente, Francisco J. Muñoz
JAD. 2014-06-04; 41(1): 273-288
DOI: 10.3233/JAD-131685

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1. J Alzheimers Dis. 2014;41(1):273-88. doi: 10.3233/JAD-131685.

Methylglyoxal produced by amyloid-β peptide-induced nitrotyrosination of
triosephosphate isomerase triggers neuronal death in Alzheimer’s disease.

Tajes M(1), Eraso-Pichot A(1), Rubio-Moscardó F(1), Guivernau B(1),
Ramos-Fernández E(1), Bosch-Morató M(1), Guix FX(1), Clarimón J(2), Miscione
GP(3), Boada M(4), Gil-Gómez G(5), Suzuki T(6), Molina H(7), Villà-Freixa J(8),
Vicente R(1), Muñoz FJ(1).

Author information:
(1)Laboratory of Molecular Physiology and Channelopathies, Departament de
Ciències Experimentals i de la Salut (DCEXS), Universitat Pompeu Fabra (UPF),
Barcelona, Spain.
(2)Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant
Pau, Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Spain.
(3)Computational Biochemistry and Biophysics Laboratory, Research Program on
Biomedical Informatics, DCEXS, IMIM/UPF, Barcelona, Spain Dipartimento di Chimica
« G. Ciamician », Universitá degli Studi di Bologna, Italy.
(4)Memory Clinic, Fundació ACE. Institut Català de Neurociències Aplicades,
Barcelona, Spain Neurology Department, Hospital Universitari Vall
d’Hebron-Institut de Recerca, Universitat Autònoma de Barcelona (VHIR-UAB),
Barcelona, Spain.
(5)IMIM (Institut Hospital del Mar d’Investigacions Mèdiques), Barcelona, Spain.
(6)Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo, Japan.
(7)Proteomics Unit, DCEXS, UPF and Centre de Regulació Genómica (CRG), Barcelona,
(8)Computational Biochemistry and Biophysics Laboratory, Research Program on
Biomedical Informatics, DCEXS, IMIM/UPF, Barcelona, Spain Escola Politécnica
Superior, Universitat de Vic, Spain.

Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to
the characteristic neurodegeneration found in Alzheimer’s disease (AD). One of
the most strongly nitrotyrosinated proteins in AD is the triosephosphate
isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency
decreased when it is nitrotyrosinated. The main aims of this study were to
analyze the impact of TPI nitrotyrosination on cell viability and to identify the
mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we
evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an
increased production of methylglyoxal (MG), a toxic byproduct of the inefficient
nitro-TPI function. The proapoptotic effects of Aβ42 oligomers, such as
decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax,
were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F
and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma
cells transfected with the double mutant TPI consistently triggered MG production
and a decrease in cell viability due to apoptotic mechanisms. Our data show for
the first time that MG is playing a key role in the neuronal death induced by Aβ
oligomers. This occurs because of TPI nitrotyrosination, which affects both
tyrosines associated with the catalytic center.

DOI: 10.3233/JAD-131685
PMID: 24614897 [Indexed for MEDLINE]

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