The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.
Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimerʼs disease
Abstract
Inhibition of protein translation is a mode of inducing neuronal apoptosis and neurodegeneration in Alzheimer's disease (AD). Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) terminates global protein translation and induces apoptosis. We examined whether this signaling pathway occurs in degenerating neurons of AD. Brain sections from young individuals, age-matched control individuals and AD patients were examined for immunoreactivity of phosphorylated eIF2alpha by immunohistochemical analysis. While young brain sections did not display and age-matched brain sections have mild immunoreactive positive cells, AD brain sections revealed intense immunoreactivity for phosphorylated eIF2alpha. Most of the phosphorylated eIF2alpha immunoreactive positive neurons have high immunoreactivity for phosphorylated tau using AT8 antibody. Also, intense staining of phosphorylated eIF2alpha is associated vacuoles in degenerating neurons. This phenomenon was also observed for the immunohistochemical staining of phosphorylated PKR (double-stranded RNA-dependent protein kinase), the upstream kinase for eIF2alpha. Activation of PKR-eIF2alpha pathway is considered to be pro-apoptotic. In addition, formation of autophagy is regulated by eIF2alpha kinase. Therefore, it is concluded that phosphorylation of eIF2alpha is associated with the degeneration of neurons in AD.
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In the citing paper
“eIF2AK2 has been shown to be activated in AD brain (33)”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [33]
In the citing paper
“Some data also showed that phosphorylated PKR and eIF2α co-localized with phosphorylated τ-protein in affected neurons in AD brains [50].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [50]
In the citing paper
“previous reports revealed that phosphorylation of PKR and eIF2α was associated with degenerating neurons in AD brains [50, 95, 96].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [50]
In the citing paper
“Several studies revealed an increased PKR expression with ageing [47] or in neurodegenerative diseases such as AD, Parkinson's disease, Huntington's disease [48–50]”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [50]
In the citing paper
“In brains of AD patients, Pt451-PKR was also localized in nuclei and around amyloid deposits but the Braak score was not indicated in papers [50, 95].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [50]
In the citing paper
“The control of translation through PKR/eIF2a signalling pathway is altered in AD lymphocytes as it was observed in brains of AD patients [50, 95].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [50]
In the citing paper
“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 [50]
In the citing paper
“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 [17]
Citations
Cites
PKR; a sentinel kinase for cellular stress
Williams, B. R. (1999) · Oncogene · doi:10.1038/sj.onc.1203127 · Cited by 820
Regulation of starvation- and virus-induced autophagy by the eIF2α kinase signaling pathway
Tallóczy, Z., Jiang, W., Virgin, H. W., Leib, D. A., Scheuner, D., Kaufman, R. J., Eskelinen, E., & Levine, B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012485299 · Cited by 757
Stadelmann, C., Deckwerth, T. L., Srinivasan, A. N., Bancher, C., Brück, W., Jellinger, K. A., & Lassmann, H. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65460-0 · Cited by 432
Frerichs, K. U., Smith, C. B., Brenner, M., DeGracia, D. J., Krause, G. S., Marrone, L., Dever, T. E., & Hallenbeck, J. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.24.14511 · Cited by 326
Su, J. H., Zhao, M., Anderson, A. J., Srinivasan, A. N., & Cotman, C. W. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02018-2 · Cited by 260
Brain ischemia and reperfusion activates the eukaryotic initiation factor 2α kinase, PERK
Kumar, R., Azam, S. M., Sullivan, J. M., Owen, C. R., Cavener, D. R., Zhang, P., Ron, D., Harding, H. P., Chen, J.-J., Han, A., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00387.x · Cited by 212
Boutajangout, A., Leroy, K., Authelet, M., Anderton, B. H., Brion, J., & Woodgett, J. R. (2002) · Acta Neuropathologica · doi:10.1007/s004010100435 · Cited by 190
Chang, R. C., Suen, K., Ma, C., Elyaman, W., Ng, H., & Hugon, J. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01237.x · Cited by 180
Self-citationTranslation Inhibition in Apoptosis
Saelens, X., Kalai, M., & Vandenabeele, P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103674200 · Cited by 177
In Situ Immunodetection of Neuronal Caspase-3 Activation in Alzheimer Disease
Selznick, L. A., Holtzman, D. M., Han, B. H., Gökden, M., Srinivasan, A. N., Johnson, E. M., & Roth, K. A. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199909000-00012 · Cited by 160
Research works printed but not linked: 3
- Bondareff, 1991, Am J Pathol, 139, 641
- Hugon, 2000, J Neural Transm Suppl, 59, 125
- Suen, 2002, Soc Neurosci Abstr, 892.1, 1
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The integrated stress response: From mechanism to disease
Costa-Mattioli, M., & Walter, P. (2020) · Science · doi:10.1126/science.aat5314 · Cited by 1,617
Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau
Caccamo, A., Majumder, S., Richardson, A., Strong, R., & Oddo, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.100420 · Cited by 881
Autophagy: in sickness and in health
Cuervo, A. M. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.12.002 · Cited by 828
Suppression of eIF2α kinases alleviates Alzheimer's disease–related plasticity and memory deficits
Ma, T., Trinh, M. A., Wexler, A. J., Bourbon, C., Gatti, E., Pierre, P., Cavener, D. R., & Klann, E. (2013) · Nature Neuroscience · doi:10.1038/nn.3486 · Cited by 575
The unfolded protein response is activated in Alzheimer’s disease
Hoozemans, J. J. M., Veerhuis, R., van Haastert, E. S., Rozemüller, A. J. M., Baas, F., Eikelenboom, P., & Scheper, W. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1038-0 · Cited by 549
Metadata
- Authors
- Chang, R. C. C., Wong, A. K. Y., Ng, H.-K., & Hugon, J.
- Affiliations
- University of Hong Kong (HK)
- Chinese University of Hong Kong (HK)
- Venue
- NeuroReport
- Published
- 2002-12
- Volume
- 13
- Issue
- 18
- Pages
- 2429-2432
- ISSN
- 0959-4965 (ISSN-L)
- OpenAlex
- W2013806485
- Cited by
- 289
- References
- 23
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 11 · 2023: 12 · 2022: 14 · 2021: 21 · 2020: 19 · 2019: 15 · 2018: 17 · 2017: 9 · 2016: 13 · 2015: 24 · 2014: 13 · 2013: 11 · 2012: 13
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroreport (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- eIF2α phosphorylation, Alzheimer's disease, neurodegeneration, protein translation inhibition, neuronal apoptosis, tau phosphorylation, autophagy
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Female, Fluorescent Antibody Technique, Fluorescent Dyes, Humans, Male, Nerve Degeneration, Phosphorylation, Signal Transduction, Eukaryotic Initiation Factor-2
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