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Cited by 95Alzheimer's disease research and treatmentsEndoplasmic Reticulum Stress and DiseaseCell death mechanisms and regulation

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

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Suen, Ka-Chun, Yu, Man-Shan, So, Kwok-Fai, Chang, Raymond Chuen-Chung, Hugon, Jacques·2003·Journal of Biological Chemistry
DOI 10.1074/jbc.m306503200
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Abstract

One of the hallmarks of Alzheimer's disease is extracellular accumulation of senile plaques composed primarily of aggregated beta-amyloid (Abeta) peptide. Treatment of cultured neurons with Abeta peptide induces neuronal death in which apoptosis is suggested to be one of the mechanisms. We have demonstrated previously that Abeta peptide induces activation of double-stranded RNA-dependent serine/threonine protein kinase (PKR) and phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) in neurons in vitro. Degenerating neurons in brain tissues from Alzheimer's disease patients also displayed high immunoreactivity for phosphorylated PKR and eIF2alpha. Our previous data have also indicated that PKR plays a significant role in mediating Abeta peptide-induced neuronal death, because neurons from PKR knockout mice and neuroblastoma SH-SY5Y cells stably transfected with dominant negative mutant of PKR are less susceptible to Abeta peptide toxicity. Therefore, it is important to understand how PKR is activated by Abeta peptide. We report here that inhibition of caspase-3 activity reduces phosphorylation of PKR and to a certain extent, cleavage of PKR and eIF2alpha in neurons exposed to Abeta peptide. Calcium release from the endoplasmic reticulum and activation of caspase-8 are the upstream signals modulating the caspase-3-mediated activation of PKR by Abeta peptide. Although in other systems HSP90 serves as a repressor for PKR, it is unlikely the candidate for caspase-3 to affect PKR activation in neurons after Abeta peptide exposure. Elucidation of the upstream pathways for PKR activation can help us to understand how this kinase participates in Abeta peptide neurotoxicity and to develop effective neuroprotective strategy.

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  • 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 [28]

    The Abstract states that activated PKR phosphorylates eIF2α, and the Discussion links phosphorylated PKR and eIF2α to degenerating neurons in AD patients. The paper does not establish p53 as a PKR target in AD; a search for p53 found no passage addressing that part of the claim. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Aβ neurotoxicity is associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure in vitro.

    “Another report demonstrated in vitro that Aβ neurotoxicity was associated with an increased PKR and eIF2α phosphorylation linked to increased intracellular calcium and caspase-8 activation following Aβ exposure [28, 30].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [28]

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Authors
Suen, K.-C., Yu, M.-S., So, K.-F., Chang, R. C.-C., & Hugon, J.
Affiliations
University of Hong Kong (HK)
Corresponding author
  • Chang, Raymond Chuen-Chung
  • Hugon, Jacques
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2003-12
Volume
278
Issue
50
Pages
49819-49827
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m306503200
OpenAlex
W2092393699
Cited by
95
References
2
Citations by year
2025: 2 · 2022: 1 · 2021: 1 · 2019: 2 · 2018: 5 · 2017: 1 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 2
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
PKR, beta-amyloid peptide, Alzheimer's disease, neuronal cell death, caspase-3, caspase-8, eIF2α phosphorylation, endoplasmic reticulum calcium release, apoptosis, neurotoxicity
MeSH terms
Animals, Brain, Calcium, Cells, Cultured, Endoplasmic Reticulum, Enzyme Activation, Enzyme Inhibitors, Cricetinae, Humans, Models, Biological, Neurons, Peptides, Phosphorylation, Precipitin Tests, Time Factors, Transfection, Blotting, Western, Signal Transduction, Eukaryotic Initiation Factor-2, Amyloid beta-Peptides, CHO Cells, Rats, Sprague-Dawley, Apoptosis, HSP90 Heat-Shock Proteins, eIF-2 Kinase, Caspases, Mice, Rats, Caspase 3, Caspase 8, Caspase 9, Caspase Inhibitors

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