Upstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicity

Suen, Ka-Chun; Yu, Man-Shan; So, Kwok-Fai; Chang, Raymond Chuen‐Chung; Hugon, Jacques

doi:10.1074/jbc.m306503200

Cited by 91 publications

(87 citation statements)

References 70 publications

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“…Ab has been reported to phosphorylate eIF-2a via PKR activation in neuronal cells (Chang et al, 2002b;Suen et al, 2003). We found that minocycline reduced PKR phosphorylation at threonine 446 and 451 induced by Ab 1-42 treatment (Figure 1d).…”

Section: Discussionmentioning

confidence: 56%

“…PKR is known to play a crucial role in mediating Ab-induced neuronal death because primary cortical neurons from PKR KO mice and neuroblastoma SH-SY5Y cells stably transfected with dominant-negative PKR mutants are less susceptible to Ab toxicity (Chang et al, 2002b). Activated PKR can phosphorylate eIF2a at serine 51 (Suen et al, 2003). Phosphorylation of eIF2a that could increase owing to many factors by Ab 1-42 , APP-CTs expression or Swedish APP transgenes in Tg2576 mice, might contribute to impairment in synaptic plasticity and cognitive function before causing neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we checked whether minocycline affects the upregulated p-eIF-2a induced by Ab 1-42 treatment, and found that minocycline attenuated the increases in p-eIF-2a at serine 51 by Ab 1-42 treatment in minocycline pretreated NGF-differentiated PC 12 cells by about 20%, whereas eIF2a was not affected by Ab 1-42 or by minocycline (Figure 1c). Ab is reported to phosphorylate eIF-2a via PKR activation in neuronal cells (Chang et al, 2002a;Suen et al, 2003). We investigated the effects of minocycline on PKR phosphorylation caused by Ab 1-42 .…”

Section: Minocycline Inhibited the Increases In P-eif2a And Reduced Tmentioning

confidence: 99%

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Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

259

179

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Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNAdependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 a and caspase 12 activation induced by amyloid b peptide 1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 a were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid b peptide 1-42 -infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid b peptide 1-42 -infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 a is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Minocycline Inhibited the Increases In P-eif2a And Reduced Tmentioning

confidence: 99%

See 1 more Smart Citation

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

259

179

View full text Add to dashboard Cite

show abstract

“…The mechanism for activation of caspase-3/-8 is not known, but activation of caspase-3 has been suggested to be triggered by Ca 2+ release from the endoplasmic reticulum (ER) [23]. An increase in Ca 2+ concentration has also been reported to lead to activation of caspase-3 [24], while depletion of ER Ca 2+ stores has also been shown to activate PKR and induce phosphorylation of eIF2 [25].…”

Section: +mentioning

confidence: 99%

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

Russell

Siren²,

Sirén³

et al. 2008

Cancer Chemother Pharmacol

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D-Myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumour necrosis factor- / interferon-. At a concentration of 100M AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitinproteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the -subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn 2+. The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several conditions.

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“…Activation of NF-kB in the muscle of mice has been shown to lead to atrophy through increased expression of proteasome subunits and the E3 ligase, MURF1 (Cai et al, 2004). It occurs through activation of caspases-3 and -8, and the subsequent autophosphorylation of the dsRNA-dependent protein kinase (PKR) (Suen et al, 2003). Autophosphorylation of PKR in skeletal muscle has been shown to inhibit protein synthesis owing to phosphorylation of eukaryotic initiation factor-2 (eIF2) on the a-subunit, and increased protein degradation through the NF-kBmediated induction of the ubiquitin -proteasome pathway (Eley and Tisdale, 2007).…”

Section: Discussionmentioning

confidence: 99%

The role of zinc in the anti-tumour and anti-cachectic activity of D-myo-inositol 1,2,6-triphosphate

Russell

Siren²,

Siren³

et al. 2010

Br J Cancer

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BACKGROUND: D-myo-inositol-1,2,6-triphosphate (a-trinositol, AT) is a polyanionic molecule capable of chelating divalent metal ions with anti-tumour and anti-cachectic activity in a murine model. METHODS: To investigate the role of zinc in this process, mice bearing cachexia-inducing MAC16 tumour were treated with AT, with or without concomitant administration of ZnSO 4 . RESULTS: At a dose of 40 mg kg À1 , AT effectively attenuated both weight loss and growth of the MAC16 tumour, and both effects were attenuated by co-administration of Zn 2 þ . The concentration of zinc in gastrocnemius muscle increased with increasing weight loss, whereas administration of AT decreased the levels of zinc in plasma, skeletal muscle and tumour, which were restored back to control values after administration of ZnSO 4 . CONCLUSION: These results suggest that zinc is important in both tumour growth and cachexia in this animal model.

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Upstream Signaling Pathways Leading to the Activation of Double-stranded RNA-dependent Serine/Threonine Protein Kinase in β-Amyloid Peptide Neurotoxicity

Cited by 91 publications

References 70 publications

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

The role of zinc in the anti-tumour and anti-cachectic activity of D-myo-inositol 1,2,6-triphosphate

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