Quinolinic acid in the pathogenesis of Alzheimer's disease.
We propose that the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly quinolinic acid (QUIN), may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we demonstrated that after 72 hours amyloid peptide (Abeta) 1-42 induced indoleamine 2,3-dioxygenase (IDO) expression and in a significant increase in production of QUIN by human macrophages and microglia. In contrast, Abeta11-40 and Prion peptide (PrP) 106-126 did not induce any significant increase in QUIN production. We also investigated the potential modulatory effect of QUIN and kynurenic acid (KYNA) on Abeta11-42 and Abeta1-40 aggregation. After 24 and 120 hours, we did not observe any significant difference in the level of aggregation compared to the control (Abeta alone). Abeta has been shown to induce IL1-beta mRNA expression by human foetal astrocytes and macrophages. We demonstrate that QUIN has the same effect. Interestingly, IL-1beta has been found in association with plaques in AD. All together these data imply that QUIN may be, locally, one of the factors involved in the pathogenesis of neuronal damage in AD.
Guillemin
Gilles J
GJ
Centre for Immunology, St Vincent's Hospital, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
Williams
Kieran R
KR
Smith
Danielle G
DG
Smythe
George A
GA
Croitoru-Lamoury
Juliana
J
Brew
Bruce J
BJ
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007375:Interleukin-1 / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008959:Models, Neurological; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D017378:Quinolinic Acid / Q000378:metabolism* / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics
D016229:Amyloid beta-Peptides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007375:Interleukin-1; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid