Abstract
To assess the role of the kynurenine pathway in the pathology of Alzheimer's disease (AD), the expression and localization of key components of the kynurenine pathway including the key regulatory enzyme tryptophan 2,3 dioxygenase (TDO), and the metabolites tryptophan, kynurenine, kynurenic acid, quinolinic acid and picolinic acid were assessed in different brain regions of triple transgenic AD mice. The expression and cell distribution of TDO and quinolinic acid, and their co-localization with neurofibrillary tangles and senile β amyloid deposition were also determined in hippocampal sections from human AD brains. The expression of TDO mRNA was significantly increased in the cerebellum of AD mouse brain. Immunohistochemistry demonstrated that the density of TDO immuno-positive cells was significantly higher in the AD mice. The production of the excitotoxin quinolinic acid strongly increased in the hippocampus in a progressive and age-dependent manner in AD mice. Significantly higher TDO and indoleamine 2,3 dioxygenase 1 immunoreactivity was observed in the hippocampus of AD patients. Furthermore, TDO co-localizes with quinolinic acid, neurofibrillary tangles-tau and amyloid deposits in the hippocampus of AD. These results show that the kynurenine pathway is over-activated in AD mice. This is the first report demonstrating that TDO is highly expressed in the brains of AD mice and in AD patients, suggesting that TDO-mediated activation of the kynurenine pathway could be involved in neurofibrillary tangles formation and associated with senile plaque. Our study adds to the evidence that the kynurenine pathway may play important roles in the neurodegenerative processes of AD.
Highlights
During neuroinflammation, 95% of the cerebral pool of the essential amino acid tryptophan (Trp) is catabolized through the kynurenine pathway (KP) leading to the formation of several neuroactive metabolites (Fig. 1)
The initial step of the KP is mainly regulated by two key enzymes: indoleamine 2,3-dioxygenase 1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), which differ in their tissue localization and regulation [3]
We have demonstrated that IDO-1 expression and quinolinic acid (QUIN) production are increased in Alzheimer’s disease (AD) hippocampus [14] and that QUIN leads to tau hyperphosphorylation in human cortical neurons [15]
Summary
95% of the cerebral pool of the essential amino acid tryptophan (Trp) is catabolized through the kynurenine pathway (KP) leading to the formation of several neuroactive metabolites (Fig. 1). The downstream metabolites of the KP and especially quinolinic acid (QUIN) an agonist of NMDA receptors [1,2], have been implicated in the pathophysiology of several brain diseases. The initial step of the KP is mainly regulated by two key enzymes: indoleamine 2,3-dioxygenase 1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), which differ in their tissue localization and regulation [3]. IDO-1 is widely expressed in all tissues and is involved in the metabolism of Trp [4,5]. IDO-1 plays a key role in the regulation of the CNS immune response [7]
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