Effect of quinolinic acid on human astrocytes morphology and functions

Implications in Alzheimer's disease

Ka K. Ting, Bruce J. Brew, Gilles J. Guillemin*

*Corresponding author for this work

Research output: Contribution to journalArticle

96 Citations (Scopus)
5 Downloads (Pure)

Abstract

The excitotoxin quinolinic acid (QUIN) is synthesized through the kynurenine pathway (KP) by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD). The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-and#947; and TNF-and#945; on primary human astrocytes. We found that QUIN induces IL-1and#946; expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls; features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS) activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

Original languageEnglish
Article number36
Pages (from-to)1-13
Number of pages13
JournalJournal of Neuroinflammation
Volume6
DOIs
Publication statusPublished - 10 Dec 2009
Externally publishedYes

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