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Cited by 257Alzheimer's disease research and treatmentsTryptophan and brain disordersNeuroinflammation and Neurodegeneration Mechanisms

The Excitotoxin Quinolinic Acid Induces Tau Phosphorylation in Human Neurons

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Rahman, Abdur, Ting, Kaka, Cullen, Karen M., Braidy, Nady, Brew, Bruce J., Guillemin, Gilles J.·2009·PLoS ONE
DOI 10.1371/journal.pone.0006344PMC PMC2709912
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Abstract

Some of the tryptophan catabolites produced through the kynurenine pathway (KP), and more particularly the excitotoxin quinolinic acid (QA), are likely to play a role in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the KP is over activated in AD brain and that QA accumulates in amyloid plaques and within dystrophic neurons. We hypothesized that QA in pathophysiological concentrations affects tau phosphorylation. Using immunohistochemistry, we found that QA is co-localized with hyperphosphorylated tau (HPT) within cortical neurons in AD brain. We then investigated in vitro the effects of QA at various pathophysiological concentrations on tau phosphorylation in primary cultures of human neurons. Using western blot, we found that QA treatment increased the phosphorylation of tau at serine 199/202, threonine 231 and serine 396/404 in a dose dependent manner. Increased accumulation of phosphorylated tau was also confirmed by immunocytochemistry. This increase in tau phosphorylation was paralleled by a substantial decrease in the total protein phosphatase activity. A substantial decrease in PP2A expression and modest decrease in PP1 expression were observed in neuronal cultures treated with QA. These data clearly demonstrate that QA can induce tau phosphorylation at residues present in the PHF in the AD brain. To induce tau phosphorylation, QA appears to act through NMDA receptor activation similar to other agonists, glutamate and NMDA. The QA effect was abrogated by the NMDA receptor antagonist memantine. Using PCR arrays, we found that QA significantly induces 10 genes in human neurons all known to be associated with AD pathology. Of these 10 genes, 6 belong to pathways involved in tau phosphorylation and 4 of them in neuroprotection. Altogether these results indicate a likely role of QA in the AD pathology through promotion of tau phosphorylation. Understanding the mechanism of the neurotoxic effects of QA is essential in developing novel therapeutic strategies for AD.

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  • In the Tg2576 mouse model of AD, characterized by β-amyloid accumulation, QUIN may contribute to increased KYN signaling.

    “This suggests that in the Tg2576 mouse model of AD, characterized by β-amyloid accumulation, QUIN may contribute to increased KYN signaling [18,58].”

    From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [58]

    The Introduction (page unavailable) says the kynurenine pathway is activated in AD brain, leading to increased quinolinic acid production. The Abstract (page unavailable) also reports quinolinic acid accumulation in amyloid plaques. Neither passage addresses Tg2576 mice or shows that quinolinic acid contributes to increased kynurenine-pathway signaling; the reported direction is pathway activation leading to quinolinic acid production. (LLM, conf=0.83)

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References 70 · Cited by 257

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Authors
Rahman, A., Ting, K., Cullen, K. M., Braidy, N., Brew, B. J., & Guillemin, G. J.
Affiliations
  • UNSW Sydney (AU)
  • The University of Sydney (AU)
  • St Vincent's Hospital Sydney (AU)
Corresponding author
Guillemin, Gilles J.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2009-07-22
Volume
4
Issue
7
Pages
e6344
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0006344
PMC
PMC2709912
OpenAlex
W2028303382
Cited by
257
References
70
Citations by year
2026: 18 · 2025: 12 · 2024: 19 · 2023: 8 · 2022: 16 · 2021: 19 · 2020: 16 · 2019: 16 · 2018: 14 · 2017: 12 · 2016: 23 · 2015: 18 · 2014: 16 · 2013: 12 · 2012: 12
FWCI
8.42
Type
journal article
Language
en
Update notices
expression_of_concern (2024-11-14)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Judith Jane Mason and Harold Stannett Williams Memorial Foundation
  • University of Melbourne
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
quinolinic acid, tau phosphorylation, kynurenine pathway, tryptophan catabolites, Alzheimer's disease, excitotoxicity, NMDA receptor, memantine, protein phosphatase 2A, protein phosphatase 1, hyperphosphorylated tau, neurotoxicity, gene expression profiling, neuroprotection
MeSH terms
Alzheimer Disease, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Humans, Immunohistochemistry, Neurons, Phosphorylation, Blotting, Western, Polymerase Chain Reaction, Receptors, N-Methyl-D-Aspartate, tau Proteins, Quinolinic Acid, Immunoprecipitation, Protein Phosphatase 2

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