1 December 2011
I read with interest the recent article by Dobos et al.  on the role of indoleamine 2,3-dioxygenase (IDO) in depression (MDD), suggestive of overlaps to the role of IDO in Alzheimer’s disease (AD). The kynurenine pathways are an area of extensive current research, given the links to stress, prodromal MDD, emergent seizures, and neurodegeneration . I wondered as to whether the authors had considered a role for the aryl hydrocarbon receptor (AHr) and circadian genes in the regulation of IDO.
Recent data suggests a significant role for the AHr in the induction of IDO in different cell types . The AHr is activated by kynurenine , suggesting a possible positive feedback loop whereby IDO, or maybe more likely TDO (tryptophan 2,3-dioxygenase), induced kynurenine would activate the AHr, leading to IDO induction. In both MDD and AD, increased HPA axis activity enhances cortisol induction of TDO in astrocytes and some neurons. The release of kynurenine would then activate microglia AHr, leading to the induction of IDO and quinolinic acid (QA). QA is excitotoxic, increasing neuronal loss and contributing to emergent seizures . QA is increased in some central nervous system regions in stress-induced depression in rodents  and in MDD patients . Such a scenario suggests a powerful role for the intercommunication between glia, via the kynurenine pathway products, in the overlap of MDD and AD.
Circadian dysregulation is a relevant factor in both AD and mood disorders [7,8]. Circadian genes have a role in the regulation of the IDO pathways. The circadian gene Period1 is known to interact with, and modulate the activity of, the AHr . TCDD, the classical activator of the AHr, shows dramatic differences between day and night AHr inductions . If indeed the AHr is a significant inducer of IDO in microglia, some of the circadian gene and melatonin links to AD and MDD may be driving significant alterations in glia kynurenine pathway activity, with impacts on neuronal activity and survival.
There are likely many different facets and etiologies to MDD. Somatization significantly overlaps with MDD, and has been shown recently by Michael Maes and colleagues to be differentiated from MDD on the basis of the patterning of kynurenine pathway products . Specifically somatization shows increased kynurenine and relatively decreased kynurenic acid in comparison to MDD. This could suggest that somatization is a confounding factor in conceptualizations of overlaps in the biochemical underpinnings of MDD and AD.
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 Dobos N, de Vries FF, Kema IP, Patas K, OPrins M, Nijholt IM, Dierckx RA, Korf J, den Boer JA, Luiten PG, Eisel UL (2012) The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis 28, 905-915.
 Anderson G, Ojalla JO (2010) Alzheimer’s and seizures: interleukin-18, indoleamine 2,3-dioxygenase and quinolinic acid. Int J Trytophan Res 3, 169-173.
 Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2010) Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci U S A 107, 19961-19966.
 Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203.
 Laugeray A, Launay JM, Callebert J, Surget A, Belzung C, Barone PR (2010) Peripheral and cerebral metabolic abnormalities of the tryptophan- kynurenine pathway in a murine model of major depression. Behav Brain Res 210, 84-91.
 Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer zu Schwabedissen L, Bogerts B, Myint AM (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulated gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflamm 8, 94.
 Cermakian N, Lamont EW, Boudreau P, Boivin DB (2011) Circadian clock gene expression in brain regions of Alzheimer’s disease patients and control subjects. J Biol Rhythms 26, 160-170.
 Soria V, Martínez-Amorós E, Escaramís G, Valero J, Pérez-Egea R, García C, Gutiérrez-Zotes A, Puigdemont D, Bayés M, Crespo JM, Martorell L, Vilella E, Labad A, Vallejo J, Pérez V, Menchón JM, Estivill X, Gratacòs M, Urretavizcaya M (2010) Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder. Neuropsychopharmacology 35, 1279-1289.
 Qu X, Metz RP, Porter WW, Cassone VM, Earnest DJ (2009) Disruption of period gene expression alters the inductive effects of dioxin on the AhR signaling pathway in the mouse liver. Toxicol Appl Pharmacol 234, 370-377.
 Qu X, Metz RP, Porter WW, Neuendorff N, Earnest BJ, Earnest DJ (2010) The clock genes period 1and period 2 mediate diurnal rhythms in dioxin-induced Cyp1A1 expression in the mouse mammary gland and liver. Toxicol Lett 196, 28-32.
 Maes M, Galecki P, Verkerk R, Rief W (2011) Somatization, but not depression, is characterized by disorders in the tryptophan catabolite (TRYCAT) pathway, indicating increased indoleamine 2,3-dioxygenase and lowered kynurenine aminotransferase activity. Neuro Endocrinol Lett 32, 264-273.
Response to Letter to the
Response to Letter to the Editor from Anderson
We greatly appreciate the comment of Dr. George Anderson on our recently published paper in the Journal of Alzheimer’s Disease. Although we were aware of the fact that in Alzheimer’s disease and in major depression the circadian regulation is disturbed, we did not focus in this study on the role of circadian genes and the aryl hydrocarbon receptors in the regulation of indoleamine 2,3-dioxygenase (IDO). However, we were pleased to read Dr. Anderson’s remarks and discussion, and, indeed, it might be worthwhile including circadian aspects in future models of depression and Alzheimer’s disease.
Niki Dobos, Ulrich L. M. Eisel, Paul G. M. Luiten