Mass spectrometric detection of quinolinic acid in microdissected Alzheimer's disease plaques

Gilles J. Guillemin, Bruce J. Brew, Claire E. Noonan, Toby G. Knight, George A. Smythe, Karen M. Cullen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

Inflammation, chiefly in the form of activated microglia, is a feature of Alzheimer's disease (AD) pathology. The kynurenine pathway of tryptophan degradation is activated in inflammation. One of the end products of the pathway, quinolinic acid (QUIN), is a potent excitotoxin and is produced by macrophages and microglia. In our study of AD post-mortem brain tissue, we investigated the presence of QUIN in plaques. We used QUIN immunohistochemistry in 45-μm sections of AD and control brain tissue. Then, to confirm the immunohistochemical findings, plaques were isolated using laser capture microdissection and analysed for QUIN using mass spectroscopy. In AD tissue, QUIN-immunoreactivity was detected in cortical microglia, astrocytes and neurons, with microglial and astrocytic expression of QUIN highest in the perimeter of senile plaques. Whole brain extracts of AD have not previously shown a significant up-regulation of QUIN, however, the lesions of AD are microlocal and evolve over time. To confirm the presence of QUIN in senile plaques and provide some quantitative estimates, we microdissected lesions from AD hippocampus using light microscopy and laser capture and then used gas chromatography-mass spectroscopy for QUIN. QUIN was enriched in plaques but was not detected in periplaque regions or in control brain tissue free from plaques. These results provide a platform on which to assay the evolving presence of QUIN in the plaque. Our data show that QUIN is a candidate factor in the complex and multi-factorial cascade of AD neurodegeneration. Tempering the action of this excitotoxin with kynurenine pathway inhibitors may open a therapeutic door for patients in active stages of the disease.

Original languageEnglish
Pages (from-to)404-408
Number of pages5
JournalInternational Congress Series
Volume1304
DOIs
Publication statusPublished - 1 Nov 2007
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Hippocampus
  • Laser capture microdissection
  • Neuroinflammation
  • Quinolinic acid
  • Senile plaques

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