Regulation of promoter activity of the APP gene by cytokines and growth factors: Implications in Alzheimer's disease

Y. W. Ge, Debomoy Lahiri

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

One of the major pathological hallmarks of Alzheimer's disease (AD) is the presence of brain depositions of senile plaques that are primarily composed of potentially toxic amyloid β-peptide (Aβ), which is generated from a family of Aβ-containing precursor proteins (APP; 695-770 amino acids). The role of inflammatory cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to study the effects of these factors on the regulation of APP gene expression. Here we compared APP promoter activity in the presence of different growth factors and cytokines such as brain-derived neurotrophic factor (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3), transforming growth factor (TGF-β1), and tumor necrosis factor (TNF-α1). PC12 neuronal cells, which were treated separately with these agents, were transfected with the construct containing either 190 bp APP proximal promoter region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp APP 5′-untranslated region (UTR, +50 to 144) or other 5′-UTR-deleted regions. Each construct was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF-β1, or TNF-α stimulated reporter activity in a promoter/UTR-specific manner. Transfection with the complete -46 to 144 region retained the maximum stimulatory activity for any treatment tested in PC12 cells. These results suggest that the regulatory elements of the APP gene respond to the stimulation of different growth factors, cytokines, and interleukins. This is consistent with the effects of the different growth factors, cytokines, and interleukins on APP message and protein levels.

Original languageEnglish
Pages (from-to)463-467
Number of pages5
JournalAnnals of the New York Academy of Sciences
Volume973
StatePublished - 2002

Fingerprint

Interleukins
PC12 Cells
Intercellular Signaling Peptides and Proteins
Alzheimer Disease
Genes
Cytokines
Untranslated Regions
5' Untranslated Regions
Brain-Derived Neurotrophic Factor
Nerve Growth Factor
Interleukin-1
Protein Precursors
Poisons
Transcription Initiation Site
Amyloid Plaques
Gene Expression Regulation
Transforming Growth Factors
Chloramphenicol
Transferases
Amyloid

Keywords

  • Alzheimer's disease
  • APP gene
  • Cytokines
  • Growth factors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Regulation of promoter activity of the APP gene by cytokines and growth factors: Implications in Alzheimer's disease",
abstract = "One of the major pathological hallmarks of Alzheimer's disease (AD) is the presence of brain depositions of senile plaques that are primarily composed of potentially toxic amyloid β-peptide (Aβ), which is generated from a family of Aβ-containing precursor proteins (APP; 695-770 amino acids). The role of inflammatory cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to study the effects of these factors on the regulation of APP gene expression. Here we compared APP promoter activity in the presence of different growth factors and cytokines such as brain-derived neurotrophic factor (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3), transforming growth factor (TGF-β1), and tumor necrosis factor (TNF-α1). PC12 neuronal cells, which were treated separately with these agents, were transfected with the construct containing either 190 bp APP proximal promoter region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp APP 5′-untranslated region (UTR, +50 to 144) or other 5′-UTR-deleted regions. Each construct was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF-β1, or TNF-α stimulated reporter activity in a promoter/UTR-specific manner. Transfection with the complete -46 to 144 region retained the maximum stimulatory activity for any treatment tested in PC12 cells. These results suggest that the regulatory elements of the APP gene respond to the stimulation of different growth factors, cytokines, and interleukins. This is consistent with the effects of the different growth factors, cytokines, and interleukins on APP message and protein levels.",
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