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

Abstract

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.

• Authors: 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
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 41 Issue 1 Pg. 273-88 ( 2014) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 24614897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• amyloid beta-protein (1-42)
• Pyruvaldehyde
• Triose-Phosphate Isomerase

Topics

• Aged
• Alzheimer Disease (genetics, physiopathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Apoptosis (genetics, physiology)
• Brain (physiopathology)
• Cell Line, Tumor
• Cell Survival (genetics, physiology)
• Computer Simulation
• Female
• Humans
• Male
• Mice, Transgenic
• Middle Aged
• Models, Molecular
• Neurons (physiology)
• Peptide Fragments (metabolism)
• Presenilin-1 (genetics)
• Pyruvaldehyde (metabolism)
• Triose-Phosphate Isomerase (genetics, metabolism)