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Cathepsin L plays a role in quinolinic acid-induced NF-?b activation and excitotoxicity in rat striatal neurons.

ABSTRACT: The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-?B) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to assess the contribution of cathepsin L to QA-induced striatal neuron death. Western blot analysis and cathepsin L activity assay were used to assess the changes in the levels of cathepsin L after QA treatment. Western blot analysis was used to assess the changes in the protein levels of inhibitor of NF-?B alpha isoform (I?B-?) and phospho-I?B alpha (p-I?B?) after QA treatment. Immunohistochemical analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced NF-?B. Western blot analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced I?B-? phosphorylation and degradation, changes in the levels of IKK?, p-IKK?, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced loss of striatal neurons were strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced degradation of I?B-?, NF-?B nuclear translocation, up-regulation of NF-?B responsive gene TP53, and activation of caspase-3 was strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced increases in beclin 1, LC3II/LC3I, and down-regulation of p62 were reduced by Z-FF-FMK or NaphthaCHO. These results suggest that cathepsin L is involved in glutamate receptor-induced NF-?B activation. Cathepsin L inhibitors have neuroprotective effects by inhibiting glutamate receptor-induced I?B-? degradation and NF-?B activation.

SUBMITTER: Wang YR

PROVIDER: S-EPMC3779166 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Cathepsin L plays a role in quinolinic acid-induced NF-Κb activation and excitotoxicity in rat striatal neurons.

Wang Yan-Ru YR Qin Shu S Han Rong R Wu Jun-Chao JC Liang Zhong-Qin ZQ Qin Zheng-Hong ZH Wang Yan Y

PloS one 20130920 9

The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-κB) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to ...[more]

PMID: 24073275

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Project description: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.

Dataset Information

Cathepsin L plays a role in quinolinic acid-induced NF-?b activation and excitotoxicity in rat striatal neurons.

Publications

Cathepsin L plays a role in quinolinic acid-induced NF-Κb activation and excitotoxicity in rat striatal neurons.

Similar Datasets

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