Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade

Gal Ophir, Ninette Amariglio, Jasmine Jacob-Hirsch, Ran Elkon, Gideon Rechavi, Daniel M. Michaelson

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

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-κB response elements. Direct measurement of NF-κB-regulated genes revealed that their extent of activation was greater in the apoE4 mice. Immunohistochemistry experiments revealed that microglial and NF-κB 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-κB signaling pathway.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalNeurobiology of Disease
Volume20
Issue number3
DOIs
StatePublished - Dec 2005
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank Dr. Allen Roses (Duke University, Durham, NC, USA) and Glaxo Wellcome for providing the transgenic mice and Angela Cohen for her excellent editorial assistance. This work was supported in part by grants to DMM from the Harry Stern National Center for Alzheimer's Disease, the U.S.-Binational Science Foundation, and the Eichenbaum Foundation. DMM is the incumbent of the Myriam Lebach Chair in Molecular Neurodegeneration.

Keywords

  • Alzheimer's disease
  • Apolipoprotein E4
  • Inflammation
  • LPS
  • Microarray
  • NF-κB

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