Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer's disease superior temporal lobe neocortex

J Neurosci Res. 1998 Sep 1;53(5):583-92. doi: 10.1002/(SICI)1097-4547(19980901)53:5<583::AID-JNR8>3.0.CO;2-5.


Cyclooxygenase-2 (COX-2; EC RNA message abundance in 25 control and Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-confirmed sporadic Alzheimer's disease (AD) brains is remarkably heterogeneous when compared with 55 other AD brain RNA message levels that were previously characterized (Lukiw and Bazan: J Neurosci Res 50:937-945, 1997). Examination of nuclear protein extracts (NPXTs) that were derived from control and AD-affected brain neocortical nuclei (n = 20; age range, 60-82 years; postmortem interval, 0.5-6.5 hours) by using gel shift, gel supershift, and cold oligonucleotide competition assay revealed a highly significant relationship between the extent of inflammatory transcription factor, nuclear factor (NF)-kappaB: DNA binding and the abundance of the COX-2 RNA signal (P < 0.0001; analysis of variance). No strong correlation with AP-1-DNA binding was noted (P > 0.045). These data are the first linking inflammation-related transcription factor NF-KB-DNA binding to up-regulation of transcription from a key inflammatory gene, COX-2, in both normally aging brain and in AD-affected neocortex. Systematic deletion of NF-KB-DNA binding sites in human COX-2 promoter constructs attenuates COX-2 transcriptional induction by mediators of inflammation. Strong NF-kappaB-DNA binding has been reported previously to temporally precede COX-2 gene transcription in human epithelial (A549), hamster B-cell (HIT-T15), human endothelial (HUVEC), human lymphoblast (IM9), human fibroblast (IMR90), rat glioma/mouse neuroblastoma (NG108-15), human keratinocyte (NHEK), mouse fibroblast (NIH 3T3), rat neuroblastoma (SH-SY5Y) cell lines and in mouse and rat brain hippocampus, indicating a highly conserved inflammatory signaling pathway that is common to diverse species and cell types. The mouse, rat, and human COX-2 immediate promoters, despite 7.5 x 10(7) years of DNA sequence divergence, each retain multiple recognition sites specific for NF-kappaB-DNA binding. These data suggest that basic gene induction mechanisms, which have been conserved over long periods of evolution, that increase NF-kappaB-DNA binds ing may be fundamental in driving transcription from inflammation-related genes, such as COX-2, that operate in stressed tissues, in normally aging cell lines, and in neurodegenerative disorders that include AD brain.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Aging / metabolism
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Animals
  • Consensus Sequence
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • DNA / metabolism*
  • Evolution, Molecular
  • Female
  • Humans
  • Isoenzymes / genetics*
  • Male
  • Membrane Proteins
  • Middle Aged
  • NF-kappa B / metabolism*
  • Neocortex / metabolism*
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Response Elements / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Temporal Lobe / metabolism*
  • Transcription Factor AP-1 / genetics
  • Transcriptional Activation


  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Transcription Factor AP-1
  • DNA
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases