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

doi:10.1016/j.nbd.2005.05.002

Neurobiology of Disease

Volume 20, Issue 3, December 2005, Pages 709-718

https://doi.org/10.1016/j.nbd.2005.05.002 Get rights and content

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.

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

Abstract

Section snippets

Transgenic mice

Results

Discussion

Acknowledgments

J. Lipid Res.

Biochem. Biophys. Res. Commun.

Neurochem. Int.

J. Neuroimmunol.

J. Neuroimmunol.

J. Biol. Chem.

Prog. Neuro-psychopharmacol. Biol. Psychiatry

Brain Res.

J. Biol. Chem.

Neurobiol. Dis.

Neuroscience

J. Lipid Res.

Neuroscience

J. Biol. Chem.

J. Biol. Chem.

Neurobiol. Dis.

The endocytic receptor protein LRP also mediates neuronal calcium signaling via N-methyl-d-aspartate receptors

Proc. Natl. Acad. Sci. U. S. A.

Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

Nature

Apolipoprotein-E allele-specific regulation of nitric oxide production

Ann. N. Y. Acad. Sci.

Microglial activation in Alzheimer disease, association with APOE genotype

Brain Pathol.