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.
Highlights
The kynurenine pathway (KP) (Figure 1) is a major route of Ltryptophan catabolism, resulting in the production of nicotinamide adenine dinucleotide (NAD+) and other neuroactive intermediates[1]
In order to validate the relevance of quinolinic acid (QA) in the mechanism of tau phosphorylation in the human disease, Alzheimer’s disease (AD) and control tissue were labelled for QA and tau (AT8, AT180)
Cultures treated with 1200 nM QA had less DAPI-stained neurons and a lower intensity of red staining, compared to control culture and cells treated with 500 nM QA, suggesting that QA 1200 nM is neurotoxic
Summary
The kynurenine pathway (KP) (Figure 1) is a major route of Ltryptophan catabolism, resulting in the production of nicotinamide adenine dinucleotide (NAD+) and other neuroactive intermediates[1]. Within the CNS, KP metabolites can have either neurotoxic or neuroprotective effects. Quinolinic acid (QA) is perhaps the most important in terms of biological activity. Stone and Perkins were the first to demonstrated QA ability to selectively activate neurons expressing NMDA receptors[2]. QA neurotoxicity was shown by Schwarcz[3]. QA leads acutely to human neuronal death and chronically to dysfunction by at least five mechanisms[4] and is known to be involved in several major neuroinflammatory diseases[4,5,6] including Alzheimer’s disease (AD)[7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
