Apolipoprotein E4 enhances brain inflammation by modulation of the NF-κB signaling cascade
Section snippets
Transgenic mice
Human apoE3 and apoE4 transgenic mice were generated on an apoE-deficient C57BL/6J background, utilizing human apoE3 and apoE4 transgenic constructs as previously reported (Xu et al., 1996). Briefly, cosmid libraries were constructed from lymphoblasts of humans known to be homozygous carriers for apoE3 or apoE4, after which fragments containing human regulatory sequences and the coding sequences for human apoE were used to produce the transgenic mice. The experiments were performed with
Results
Oligonucleotide chips were used to record the global gene expression profiles in the hippocampi of apoE3 and apoE4 transgenic mice at 5, 10, and 24 h following i.c.v. injection of LPS as well as in naive, non-treated mice. The extent to which the inflammatory response to LPS was affected by the apoE genotype was first investigated by comparing the levels of expression of all the genes that are assigned to inflammation-related gene ontology (GO) categories. This revealed that the basal
Discussion
The present study showed, utilizing gene microarray and clustering analysis, that the kinetics and extent of activation of brain inflammation are affected isoform-specifically by apoE. The levels of inflammation-related genes in untreated mice were similar in apoE3 and apoE4 transgenic mice. In contrast, i.c.v. injection of LPS into apoE3 transgenic mice triggered an increase in the expression of inflammation and immune-related genes, which plateaued at 5 h, whereas the corresponding response
Acknowledgments
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.
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