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Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain.
- Source :
-
PloS one [PLoS One] 2013 Apr 22; Vol. 8 (4), pp. e59749. Date of Electronic Publication: 2013 Apr 22 (Print Publication: 2013). - Publication Year :
- 2013
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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.
- Subjects :
- 3-Hydroxyanthranilate 3,4-Dioxygenase genetics
3-Hydroxyanthranilate 3,4-Dioxygenase metabolism
Aged
Aged, 80 and over
Animals
CA3 Region, Hippocampal enzymology
Carboxy-Lyases genetics
Carboxy-Lyases metabolism
Case-Control Studies
Cerebellum enzymology
Cerebral Cortex enzymology
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism
Metabolic Networks and Pathways
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Organ Specificity
Pentosyltransferases genetics
Pentosyltransferases metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Real-Time Polymerase Chain Reaction
Tryptophan metabolism
Tryptophan Oxygenase genetics
Alzheimer Disease enzymology
CA1 Region, Hippocampal enzymology
Gene Expression
Kynurenine metabolism
Tryptophan Oxygenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23630570
- Full Text :
- https://doi.org/10.1371/journal.pone.0059749