The NF-κB/Rel family of proteins mediates A β-induced neurotoxicity and glial activation

Kelly R. Bales, Yansheng Du, Richard C. Dodel, Guang Mei Yan, Elizabeth Hamilton-Byrd, Steven M. Paul

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179 Scopus citations


The β-amyloid peptide (A β) is deposited in neuritic plaques which are characteristic features of Alzheimer's disease (AD). Prominent neurodegeneration and glial activation occurs around these plaques leading to the hypothesis that A β may play a causative role in the neuronal loss and the inflammatory response associated with AD. Here we show that A β-induced toxicity of cultured fetal rat cortical neurons is associated with internucleosomal DNA fragmentation beginning just 6 h after neurons are exposed to A β. Additionally, constitutive NF-κB activity readily measured in fetal rat cortical neurons decreases in a concentration- and time-dependent fashion following exposure to A β, but there is no corresponding decrease in NF-κB mRNA or protein (p65). An upregulation of both IκBα protein and mRNA which occurs in cortical neurons exposed to A β may be responsible for retaining NF-κB in the cytoplasm accounting for the observed decrease in activated NF-κB. The latter is supported by the observation that pretreatment of cortical cultures with an antisense oligonucleotide to IκBα mRNA is neuroprotective. In contrast to cortical neurons, exposure of rat primary astroglial cultures to A β results in a concentration- and time-dependent activation of NF-κB with subsequent upregulation of IL-1β and IL-6. Our data suggest that A β-induced neurotoxicity as well as astrocyte activation may be medicated by the NF-κB/Rel family of proteins, and thus alterations in NF-κB-directed gene expression may contribute to both the neurodegeneration and inflammatory response which occur in AD.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalMolecular Brain Research
Issue number1
StatePublished - Jun 1 1998


  • Alzheimer's disease
  • Glia activation
  • IκB-α
  • NF-κB
  • β-amyloid protein


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