Neuroinflammation Group

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Current Staff & Students

Current Projects & Collaborators

The kynurenine pathway (KP)
The KP is a major degradative pathway of tryptophan (TRP) that ultimately leads to the production of NAD (Figure right). Within the brain, approximately 95% of the tryptophan absorbed in the human diet is processed by this pathway and the remaining 5% serves as a precursor to the synthesis of the neurotransmitter serotonin. Recent findings have shown that the KP is one of the major regulatory mechanisms of the immune response. Two theories have been proposed: 1) that TRP degradation suppresses T cell proliferation by dramatically depleting the supply of this critical amino acid; 2) that some downstream KP metabolites act to suppress certain immune cells. Induction of the KP regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in dendritic cells completely blocks clonal expansion of T cells. TRP depletion and IDO/KP activation have been implicated in the development of immuno-tolerance associated with pregnancy and persistence of tumors. The cellular location of the KP is only partly understood. It is complete in monocytic lineage cells, including macrophages, and microglia and we showed that it is partly present in astrocytes. The products of the KP have numerous neurotoxic and neuroprotective effects. Among them, QUIN is perhaps the most important. It leads acutely to human neuronal death and chronically to dysfunction by at least four mechanisms. Another product of the KP, kynurenic acid (KYNA), is an antagonist of all ionotropic glutamate receptors and thus can antagonize some of the effects of QUIN and other excitotoxins. It is noteworthy that in disease states where excess QUIN is produced there is insufficient KYNA to block QUIN. Several drugs that can block the KP are under investigation by our laboratory and others. For example, 4-chlorokynurenine crosses the BBB and blocks QUIN toxicity at the glycine site on NMDA receptors. KYNA analogues are in or about to enter clinical trials for treatment of epilepsy, stroke and possibly Parkinson’s disease.

Grants

The University of New South Wales
National Health & Medical Research Council
St Vincent's Clinic Foundation
Australia Academy of Science
Alzheimer's Australia
Perpetual Trust (Mason Foundation)
ALS Australia
The Rebecca Cooper Foundation

PhD & Honours Projects - topics open

Methods

Cell culture (human brain cells and various human cell lines)
RT-PCR
Real time PCR
HPLC and GC/MS
Immunocytochemistry
Immunohistochemistry
Western blot
ELISA
Transfection

Selected Publications

Primary Human Astrocytes Produce 24(S), 25-Epoxycholesterol with Implications for Brain Cholesterol Homeostasis. Jenny Wong, Carmel M. Quinn, Gilles J. Guillemin and Andrew J. Brown. J. Neurochem 2007

The involvement of astrocytes and kynurenine pathway in Alzheimer’s disease. (Review). Ka Ka Ting, Bruce Brew and Gilles Guillemin. J. Neurotoxicity 2007

Inhibition par la sérotonine de l'infection par VIH-1 dans des macrophages en culture primaire: rôle du sous-type des récepteurs sérotoninergiques 5-HT1A. Benjamin Maneglier, Odile Spreux-Varoquaux; Gilles J Guillemin; Christine Rogez-kreuz; Dominique Dormont; Charles Advenier; Pascal Clayette. Pathologie Biologie (PATBIO-D-07-00065)

Characterization of the kynurenine pathway in primary human oligodendrocytes. Chai K. Lim, George Smythe, Roland Stocker, Bruce J. Brew, Gilles J. Guillemin. International Congress Series (ICS 2007)

Chronic HIV infection leads to an Alzheimer’s disease like illness - Involvement of the kynurenine pathway. Gilles J. Guillemin and Bruce J. Brew. International Congress Series (ICS 2007)

Mass spectrometric detection of quinolinic acid in microdissected Alzheimer disease plaques. Gilles J. Guillemin, Bruce J. Brew, Claire E. Noonan, Toby G. Knight and Karen M Cullen. International Congress Series (ICS 2007)

Effect of Quinolinic acid on gene expression in human Astrocytes: Implications on Alzheimer’s disease. Ka Ka Ting, Bruce J. Brew and Gilles J. Guillemin. International Congress Series (ICS 2007)

“Novel functions for ABCG1 in the regulation of cholesterol efflux to apoE discs and neuronal generation of amyloid-beta peptide”.Woojin S. Kim,, Aldwin Suryo, Alvin Kamili, Kerry-Anne Rye, Gilles J. Guillemin, Ingrid C. Gelissen, Wendy Jessup, Andrew F. Hill and Brett Garner. J Biol Chem 2007

“Quantitation of ABCA transporter gene expression in primary human brain cells” Woojin S. Kima, , Gilles J. Guillemin, Elias N. Glaros, Chai K. Lim and Brett Garner. Neuroreport 2006.

“Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis” (Review) Gilles J. Guillemin, Vincent Meininger and Bruce J. Brew. Neurodegenerative diseases (2006) 2:166-176.

“Prolonged transcriptional silencing and CpG methylation induced by dsRNAs targeted to the HIV-1 promoter region”. Kazuo Suzuki, Toshiaki Shijuuku, Toshihiko Fukamachi, John Zaunders, Gilles Guillemin, David Cooper, & Anthony Kelleher. Journal of RNAi and Gene Silencing (2005); 1 (2).

“Quinolinic acid induces apoptosis of human astrocyte”. Gilles J. Guillemin, Lily Wang and Bruce J. Brew. J. Neuroinflammation (2005).

Indoleamine 2,3 dioxygenase and quinolinic acid in plaque and neurons in post-mortem brain tissue from Alzheimer’s disease and control cases. Gilles j. Guillemin, Bruce J. Brew, Clare Noonan, Osamu Takikawa and Karen Cullen. Neuropathology and Applied Neurobiology (2005) Aug;31(4):395-404

“Involvement of Quinolinic Acid in AIDS Dementia Complex”(Review). Gilles J. Guillemin, Stephen J Kerr and Bruce J. Brew. Neurotoxicity Research (2005); 7(1-2): 103-124.

"Prolonged transcriptional silencing and CpG methylation induced by dsRNAs targeted to the HIV-1 promoter region". Kazuo Suzuki, Toshiaki Shijuuku, Toshihiko Fukamachi, John Zaunders, Gilles Guillemin, David Cooper, & Anthony Kelleher. Journal of RNAi and Gene Silencing (2005); 1 (2).