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Cited by 52Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer’s disease and Creutzfeldt-Jakob’s disease

Ferrer, I.·2002·Neuropathology and Applied Neurobiology
DOI 10.1046/j.1365-2990.2002.t01-1-00410.x
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Abstract

Studies in vitro have shown that phosphorylated translation initiation factor 2 alpha (TIF 2 alpha) may have several functions, including regulation of protein synthesis, control of cell death and procurement of resistance to oxidative stress in nerve cells. These properties may have implications in certain human neurodegenerative diseases, such as Alzheimer's disease (AD) and Creutzfeldt-Jakob's disease (CJD), in which oxidative stress appears to be involved in the process of neurodegeneration and neurone death. Single and double-labelling immunohistochemistry to phosphorylated TIF 2 alpha, phosphorylated SAPK/JNK, phosphorylated p38, tau, Cu/Zn superoxide dismutase 1 (SOD 1) and cleaved caspase-3 (17 kDa), and in situ end-labelling of nuclear DNA fragmentation, was carried out in postmortem samples of 10 patients with AD (stages III and VI of Braak and Braak), seven patients with CJD (five cases with methionine/methionine and two cases with methionine/valine at the codon 129 of the PrP gene) and eight age-matched controls. No phosphorylated TIF 2 alpha immunoreactivity was found in control brains, but strong phosphorylated TIF 2 alpha expression was observed in subpopulations of neurones bearing neurofibrillary tangles (NFTs) or pretangles in the hippocampus, entorhinal cortex and isocortex in AD. Phosphorylated TIF 2 alpha is restricted to neurones with abnormal tau deposition, but only approximately 80% of neurones with NFTs in the hippocampus and 60% in the isocortex colocalize phosphorylated TIF 2 alpha, thus indicating that not all neurones with NFTs over-express phosphorylated TIF 2 alpha. Moreover, phosphorylated TIF 2 alpha immunoreactivity was found in a percentage of neurones expressing phosphorylated SAPK/JNK and p38, which, in turn, are involved in tau phosphorylation in AD. However, dystrophic neurites of senile plaques that contain abnormal tau and express SOD 1 are negative to antiphosphorylated TIF 2 alpha antibodies. Smooth muscle cells in blood vessels affected by amyloid angiopathy, which are putative targets of beta A 4 amyloid-derived oxidative stress, are not associated with phosphorylated TIF 2 alpha immunoreactivity. Double-staining with the method of in situ end-labelling of nuclear DNA fragmentation demonstrated no relationship between phosphorylated TIF 2 alpha expression and increased nuclear DNA vulnerability in individual cells. Moreover, no single caspase-3-immunoreactive cell in AD expressed phosphorylated TIF 2 alpha. Oxidative stress response, manifested as positive SOD 1 expression in Bergmann glia and in a few reactive astrocytes, has been demonstrated in CJD. No phosphorylated SAPK/JNK or phosphorylated p38 kinase immunoreactivity was observed in these cases. Moreover, neurones and glial cells do not over-express phosphorylated TIF 2 alpha in CJD. The present results demonstrate selective expression of phosphorylated TIF 2 alpha in subpopulations of nerve cells with abnormal tau deposition, and suggest that factors linked with tau deposition regulate protein synthesis throughout TIF 2 alpha phosphorylation in certain neurones sensitive to oxidative stress in AD.

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Crossref · 10.1046/j.1365-2990.2002.t01-1-00410.x

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  • Increased SOD expression is associated with dystrophic neurites adjacent to Aβ plaques in IHC analysis of AD models.

    “increased SOD expression is associated with dystrophic neurites adjacent to Aβ plaques in immunohistochemistry (IHC) analysis of AD models [20,21].”

    From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [21]

  • IHC for SOD1 labels areas of high oxidative stress, specifically around Aβ plaques, and is associated with dystrophic neurites.

    “IHC for SOD1 labels areas of high oxidative stress, specifically around Aβ plaques, and is associated with dystrophic neurites [21,48].”

    From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [21]

  • Elevated SOD expression is indicative of high levels of oxidative stress associated with Aβ plaques in Alzheimer's disease brains.

    “Elevated SOD expression is indicative of the high levels of oxidative stress associated with Aβ plaques in Alzheimer’s disease brains [21,48,80,104].”

    From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [21]

  • Seminal studies identified altered composition of ribosomes, abnormal expression levels of certain transcription factors, and impaired protein synthesis in cortical areas in cases with mild cognitive impairment and dementia caused by AD.

    “Seminal studies identified altered composition of ribosomes and abnormal expression levels of certain transcription factors, and impaired protein synthesis in cortical areas in cases with mild cognitive impairment and dementia caused by AD 26, 34, 62, 64, 84.”

    From Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome (2016) · cites this paper as [34]

  • Increased eIF2α correlates with increased p-eIF2α in Alzheimer's disease.

    “Increased eIF2α correlates with increased p‐eIF2α in AD as previously reported 17, 34, 49, 50.”

    From Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome (2016) · cites this paper as [34]

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Authors
Ferrer, I.
Affiliations
Universitat de Barcelona (ES)
Corresponding author
Ferrer, I.
ORCID
Ferrer, I.
Venue
Neuropathology and Applied Neurobiology
Publisher
Wiley
Published
2002-11-24
Volume
28
Issue
6
Pages
441-451
ISSN
  • 0305-1846 (ISSN-L)
  • 1365-2990
DOI
10.1046/j.1365-2990.2002.t01-1-00410.x
OpenAlex
W2025810246
Cited by
52
References
54
Citations by year
2026: 9 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 1
FWCI
1.60
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Neuropathology and Applied Neurobiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, neurofibrillary tangles, tau phosphorylation, oxidative stress, SAPK/JNK, p38 MAPK, caspase-3, superoxide dismutase 1, amyloid angiopathy, neurodegeneration, protein synthesis
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Blood Vessels, Brain, Female, Humans, Immunohistochemistry, Creutzfeldt-Jakob Syndrome, Male, Neurons, Phosphorylation, Transcription Factors, Neurofibrillary Tangles, In Situ Hybridization, Nuclear Receptor Coactivator 2, DNA Fragmentation, Plaque, Amyloid

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