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Cited by 116Alzheimer's disease research and treatmentsEndoplasmic Reticulum Stress and DiseaseNeuroinflammation and Neurodegeneration Mechanisms

Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer’s disease

Page, G., Rioux Bilan, A., Ingrand, S., Lafay-Chebassier, C., Pain, S., Perault Pochat, M.C., Bouras, C., Bayer, T. +1 more·2006·Neuroscience
DOI 10.1016/j.neuroscience.2006.01.047
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Abstract

Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed th…

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Crossref · 10.1016/j.neuroscience.2006.01.047

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  • A progressive increase of apoptotic nuclei is observed at 3, 6 and 12 months of age in APPsl/PS1 KI mice and PKR is closely co-localized with DNA strand breaks in apoptotic nuclei of hippocampal neurons.

    “A progressive increase of apoptotic nuclei is also observed at 3, 6 and 12 months of age in these mice and PKR is closely co-localized with DNA strand breaks in apoptotic nuclei of hippocampal neurons [97].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [97]

  • The up-regulation of PKR in mononuclear cells does not lead to the cell death observed in cellular models exposed to Aβ, in AD transgenic mice and in brains of AD patients.

    “Paradoxically, the up-regulation of PKR in mononuclear cells do not lead to the cell death observed in cellular models exposed to Ap, in AD transgenic mice and in brains of AD patients [50, 95, 97].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [97]

  • In brains of APPSL/PS1 KI mice, PKR was early up-regulated before the massive neuronal loss.

    “In brains of APPSL/PS1 KI mice, PKR was early up-regulated before the massive neuronal loss [97].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [97]

  • In brains of APPslPS1 KI mice, levels of phosphorylated PKR were significantly increased as early as 3 months of age, associated with intraneuronal amyloid peptide, before the massive neuronal death observed at 6 months.

    “We can remember that the levels of phosphorylated PKR were significantly increased in brains of APPslPS1 KI mice as early as 3 months of age associated with intraneuronal amyloid peptide before the massive neuronal death observed at 6 months [97].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [97]

  • In Alzheimer's disease, eIF2a and p53 are targets of PKR.

    “In AD, eIF2a and p53 are targets of PKR [28, 30, 97, 102, 129].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [97]

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Authors
Page, G., Rioux Bilan, A., Ingrand, S., Lafay-Chebassier, C., Pain, S., Perault Pochat, M. C., Bouras, C., Bayer, T., & Hugon, J.
Affiliations
  • Université de Poitiers (FR)
  • University of Geneva (CH)
  • Saarland University (DE)
Corresponding author
Page, G.
ORCID
Venue
Neuroscience
Publisher
Elsevier BV
Published
2006
Volume
139
Issue
4
Pages
1343-1354
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/j.neuroscience.2006.01.047
OpenAlex
W2024828025
Cited by
116
References
2
Citations by year
2026: 3 · 2025: 6 · 2024: 6 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 4 · 2018: 8 · 2017: 8 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 5
FWCI
4.42
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Chung Hua University
  • Université de Poitiers
  • Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche (EA 3808)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
double-stranded RNA-dependent protein kinase, neuronal cell death, Alzheimer's disease, amyloid-beta toxicity, caspase-3, hippocampal neurons, DNA strand breaks, apoptosis, neuroprotection, amyloid plaques
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Activation, Enzyme Inhibitors, Humans, Immunohistochemistry, Indoles, Membrane Proteins, Mice, Transgenic, Neuroblastoma, Neurons, Peptide Fragments, Endopeptidases, Blotting, Western, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Cell Death, eIF-2 Kinase, Caspases, In Situ Nick-End Labeling, Cell Line, Tumor, Mice, Caspase 3, Presenilin-1, Amyloid Precursor Protein Secretases

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