Role of cytokines in the gene expression of amyloid β–protein precursor: Identification of a 5'-UTR-Binding nuclear factor and its implications in Alzheimer's disease
Abstract
One of the major neuropathological characteristics of Alzheimer's disease (AD) is the brain depositions of senile plaques that are mainly composed of toxic amyloid beta-peptide (Abeta), which is generated from a family of Abeta containing precursor proteins (AbetaPP; 695-770 amino acids). The role of cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to determine the mode of action of cytokines on the regulation of betaPP gene expression. Here we studied the effect of different cytokines on the activity of 5'-untranslated region (5'-UTR) of betaPP mRNA in human astrocytic cells (U-373). We compared betaPP-5'-UTR activity in the presence of interleukin-1 (IL-1alpha and IL-1beta), transforming growth factor (TGF-beta1) and tumor necrosis factor TNF-alpha1. The astrocytic cells, which were treated separately with these agents, were transfected with either the vector (pSV2CAT) or pSV2UTR-CAT construct containing 90 bp of AbetaPP 5'-UTR +54 to 144 bp). This region was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). Our results indicate that the treatment of pSV2UTR-CAT-transfected cells with either IL-1alpha, IL-1beta, TGF-beta1 or TNF-alpha1 stimulated reporter gene activity in a factor-specific manner. This was consistent with their effects on elevating AbetaPP protein levels. Transfection of the same cells with the pSV2CAT vector lacking 5'-UTR resulted in a reduced reporter gene activity with all treatments studied. DNA-gel shift experiments indicate that the 54/144 region binds to a nuclear protein(s) in a cell type specific manner. These results suggest that 5'-UTR of the AbetaPP gene can respond to the stimulation of different cytokines, which likely regulate AbetaPP transcription and translation via regulatory elements present in the AbetaPP promoter and in 5'-UTR, respectively. The characterization of AbetaPP regulatory elements, including the 5'-UTR, will accelerate the development of novel agents against new targets for AD.
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Noxious stimuli orchestrate pathogenic gene-expression programs in stressed brain cells, linking caspase-mediated cell death pathways with apoptosis and neuronal demise.
“These noxious stimuli further orchestrate pathogenic gene-expression programs in stressed brain cells, thereby linking a cascade of caspase-mediated cell death pathways with apoptosis and neuronal demise (Bazan and Lukiw, 2002; Lahiri et al., 2003).”
From Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection (2018) · cites this paper as Lahiri et al., 2003
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“These noxious stimuli further orchestrate pathogenic gene-expression programs in stressed brain cells, thereby linking a cascade of caspase-mediated cell death pathways with apoptosis and neuronal demise (3, 33, 48).”
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Self-citationDetecting chimeric 5′/3′UTRs with cross-chromosomal splicing by bioinformatics
Zhang, Z., Zhang, Y., Shi, B., et al. (2004) · Chinese Science Bulletin · doi:10.1007/bf03184036
Ralph, S., & Clark, I. (2015) · Healthy Aging Research · doi:10.12715/har.2015.4.14
Pharmacokinetics of Novel Crystalline Buntanetap in Mice, Dogs, and Humans
Morin, A., Christie, M., Damiano, E. M., et al. (2025) · Biomolecules · doi:10.3390/biom15091299
“As a result, the stabilized IRP1-IRE complex prevents the mRNA from binding to the ribosome suppressing the translation of proteins involved in neurodegeneration [12,13].”
Transforming Growth Factor-β in Brain Functions and Dysfunctions
Vivien, D., Benchenane, K., & Ali, C. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-293-9_14
Self-citation
- Authors
- Lahiri, D. K., Chen, D., Vivien, D., Ge, Y.-W., Greig, N. H., & Rogers, J. T.
- Affiliations
- Indiana University Indianapolis (US)
- Centre National de la Recherche Scientifique (FR)
- National Institute on Aging (US)
- Harvard University (US)
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2003-04-22
- Volume
- 5
- Issue
- 2
- Pages
- 81-90
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1443476078
- Cited by
- 81
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 2 · 2013: 1 · 2012: 4
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid precursor protein
- MeSH terms
- Adrenal Gland Neoplasms, Alzheimer Disease, Animals, Astrocytoma, Brain Neoplasms, Cloning, Molecular, Gene Expression Regulation, Humans, Pheochromocytoma, Transfection, Tumor Cells, Cultured, Chloramphenicol O-Acetyltransferase, Transcriptional Activation, Cytokines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Genes, Reporter, 5' Untranslated Regions, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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