Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor

Steven W. Barger, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

A significant fraction of the β-amyloid precursor protein is proteolytically processed to yield large secreted forms (sAPP). These proteins have pleiotropic effects which potentially involve control of gene expression. We have investigated the influence of sAPP on the class of transcription factors which bind κB enhancer sequences. Transcription dependent on a κB element was enhanced by sAPP in several cell lines, as measured by expression of a transfected chloramphenicol acetyltransferase reporter gene. Secreted APP also induced an increase in κB DNA-binding activity in hippocampal neurons treated with sAPP. Both effects were mimicked by an analog of cyclic GMP and inhibited by an antagonist of cyclic GMP-dependent protein kinase. Such activation of κB-dependent transcription was correlated in two ways with the ability of sAPP to protect neuronal cells against calcium-mediated damage: (1) tumor necrosis factor β also protected against calcium-mediated insults and induced κB-dependent transcription; (2) antisense oligonucleotide-mediated reduction of an endogenous inhibitor of NF-κB activated κB-binding activity and attenuated calcium-mediated toxicity in both a neuronal cell line and in primary neurons. These findings suggest that a κB-binding transcription factor can act as a coordinator of neuroprotective gene expression in response to cytokines.

Original languageEnglish (US)
Pages (from-to)116-126
Number of pages11
JournalMolecular Brain Research
Volume40
Issue number1
DOIs
StatePublished - Aug 1996
Externally publishedYes

Fingerprint

Amyloid
Calcium
Transcription Factors
Gene Expression
Neurons
Cyclic GMP-Dependent Protein Kinases
Cell Line
Chloramphenicol O-Acetyltransferase
Amyloid beta-Protein Precursor
Antisense Oligonucleotides
Cyclic GMP
Reporter Genes
Tumor Necrosis Factor-alpha
Cytokines
DNA
Proteins

Keywords

  • β-amyloid precursor protein
  • Alzheimer's disease
  • Antisense
  • Calcium
  • cGMP
  • Free radical
  • I-κBα/MAD3
  • NF-κB
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor. / Barger, Steven W.; Mattson, Mark P.

In: Molecular Brain Research, Vol. 40, No. 1, 08.1996, p. 116-126.

Research output: Contribution to journalArticle

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