Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease.
Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-beta accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimer's diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's disease.
Bonda
David J
DJ
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
Mailankot
Maneesh
M
Stone
Jeremy G
JG
Garrett
Matthew R
MR
Staniszewska
Magdalena
M
Castellani
Rudy J
RJ
Siedlak
Sandra L
SL
Zhu
Xiongwei
X
Lee
Hyoung-gon
HG
Perry
George
G
Nagaraj
Ram H
RH
Smith
Mark A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C005045:3-hydroxykynurenine; D007737:Kynurenine