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Tajes M, Guivernau B, Ramos-Fernández E, Bosch-Morató M, Palomer E, Guix FX, Muñoz FJ

The pathophysiology of triose phosphate isomerase dysfunction in Alzheimer's disease.

Histol. Histopathol.. 2013 Jan;28(1):43-51, PMID: 23233058

Alzheimer's disease (AD), the most prevalent neurodegenerative disease worldwide, has two main hallmarks: extracellular deposits of amyloid β-peptide (Aβ) and intracellular neurofibrillary tangles composed by tau protein. Most AD cases are sporadic and are not dependent on known genetic causes; aging is the major risk factor for AD. Therefore, the oxidative stress has been proposed to initiate the uncontrolled increase in Aβ production and also to mediate the Aβ's deleterious effects on brain cells, especially on neurons from the cortex and hippocampus. The production of free radicals in the presence of nitric oxide (NO) yields to the peroxynitrite generation, a very reactive agent that nitrotyrosinates the proteins irreversibly. The nitrotyrosination produces a loss of protein physiological functions, contributing to accelerate AD progression. One of the most nitrotyrosinated proteins in AD is the enzyme triosephosphate isomerase (TPI) that isomerises trioses, regulating glucose consumption by both phosphate pentose and glycolytic pathways and thereby pyruvate production. Hence, any disturbance in the glucose supply could affect the proper brain function, considering that the brain has a high rate of glucose consumption. Besides this directly affecting to the energetic metabolism of the neurons, TPI modifications, such as mutation or nitrotyrosination, increase methylglyoxal production, a toxic precursor of advanced glycated end-products (AGEs) and responsible for protein glycation. Moreover, nitro-TPI aggregates interact with tau protein inducing the intraneuronal aggregation of tau. Here we review the relationship between modified TPI and AD, highlighting the relevance of this protein in AD pathology and the consequences of protein nitro-oxidative modifications.


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