Apolipoprotein E4 Enhances Brain Inflammation by Modulation of the NF-kappaB Signaling Cascade

Neurobiol Dis. 2005 Dec;20(3):709-18. doi: 10.1016/j.nbd.2005.05.002. Epub 2005 Jun 23.

Abstract

Apolipoprotein E4 (apoE4), the major genetic risk factor of Alzheimer's disease (AD), is associated with enhanced brain inflammation. Genome-wide gene expression profiling was employed to study the effects of apoE genotype on hippocampal gene expression in LPS-treated mice, transgenic for either apoE4 or the AD benign allele, apoE3. This revealed that the expression of inflammation-related genes following intracerebroventricular injection of LPS was significantly higher and more prolonged in apoE4 than in apoE3 transgenic mice. Clustering analysis revealed gene clusters which responded differently in apoE4 and apoE3 mice and were significantly enriched in NF-kappaB response elements. Direct measurement of NF-kappaB-regulated genes revealed that their extent of activation was greater in the apoE4 mice. Immunohistochemistry experiments revealed that microglial and NF-kappaB activation were more pronounced in apoE4 than in apoE3 mice. These findings suggest that the increased brain inflammation in apoE4 mice is related to disregulation of NF-kappaB signaling pathway.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Animals
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Brain / metabolism*
  • Brain / physiopathology
  • Disease Models, Animal
  • Encephalitis / genetics*
  • Encephalitis / metabolism
  • Encephalitis / physiopathology
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics
  • Humans
  • Injections, Intraventricular
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Transgenic
  • Multigene Family / genetics
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Signal Transduction / genetics
  • Transcriptional Activation / genetics
  • Up-Regulation / genetics

Substances

  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E
  • Lipopolysaccharides
  • NF-kappa B