Methylglyoxal reduces mitochondrial potential and activates Bax and caspase-3 in neurons: Implications for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the oxidative stress generated from amyloid β-peptide (Aβ) aggregates. It produces protein nitrotyrosination, after the reaction with nitric oxide to form peroxynitrite, being triosephosphate isomerase (TPI) one of the most affected proteins. TPI is a glycolytic enzyme that catalyzes the interconversion between glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP). Methylglyoxal (MG) is a by-product of TPI activity whose production is triggered when TPI is nitrotyrosinated. MG is harmful to cells because it glycates proteins. Here we found protein glycation when human neuroblastoma cells were treated with Aβ. Moreover glycation was also observed when neuroblastoma cells overexpressed mutated TPI where Tyr165 or Tyr209, the two tyrosines close to the catalytic center, were changed by Phe in order to mimic the effect of nitrotyrosination. The pathological relevance of these findings was studied by challenging cells with Aβ oligomers and MG. A significant decrease in mitochondrial transmembrane potential, one of the first apoptotic events, was obtained. Therefore, increasing concentrations of MG were assayed searching for MG effect in neuronal apoptosis. We found a decrease of the protective Bcl2 and an increase of the proapoptotic caspase-3 and Bax levels. Our results suggest that MG is triggering apoptosis in neurons and it would play a key role in AD neurodegeneration.

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

“…In vitro incubation of neuroblastoma cells with MGO increased the activity of the proapoptotic protein Bax and caused a decrease in the antiapoptotic protein Bcl-2. In combination, these processes resulted in more apoptotic cells, which are known to play a key role in the development of Alzheimer's disease [218]. High levels of MGO also caused impairment of the oxidative status of brain mitochondria [219], which possibly contributes further to the pathogenesis of Alzheimer's disease [220].…”

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“…[21] In addition, increasing concentrations of MG were reported to trigger apoptosis by decreasing Bcl2 levels and increasing proapoptotic Caspase 3 and Bax levels, and at the end lead to neurodegeneration. [22] In another study, the effects of tenuigenin were investigated on cultured hippocampal neurons. At the end of 24 h incubation time, 100 µM MG caused 49% decrease in the number of cultured hippocampal neurons, and median toxic concentration of MG was found to be 124 µM.…”

Inhibition of neuroinflammatory nitric oxide signalling supresses protein glycation and recovers neuronal dysfunction in prion disease

“…The nitrergic post-translational modification of TPI induced by the Aβ-peptide reduces its enzymatic activity [21] leading to a shift of balance of the metabolites towards DHAP formation. Subsequently, DHAP transforms spontaneously into the cytotoxic metabolic by-product methylglyoxal [22,23]. A nitro-oxidative environment favours high levels of 3-nitrotyrosinated TPI in AD patients [21] and as a result, inhibition of this enzyme leads to non-enzymatic methylglyoxal-mediated generation of protein glycation [21] and formation of advanced glycation end products (AGE).…”