Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease.
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-gamma and TNF-alpha on primary human astrocytes. We found that QUIN induces IL-1beta 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.
Ting
Ka Ka
KK
St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia. kting@med.usyd.edu.au
Brew
Bruce J
BJ
Guillemin
Gilles J
GJ
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D007371:Interferon-gamma; D017378:Quinolinic Acid