Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway.

Published

Journal Article

Inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE4) is a major risk factor for the development of Alzheimer's disease (AD). Although the association between APOE4 and AD is well documented, the mechanism by which apolipoprotein E exerts an isoform-specific effect on neurons in disease is unknown. In this report, we demonstrate that apoE4 stimulates the transcriptional activity of cAMP-response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons. In contrast, apoE3 was unable to stimulate CREB transcriptional activity and unable to activate the ERK pathway. Elevation of intracellular Ca(2+) levels are also involved because treatment with receptor-associated protein, nifedipine, MK801, removal of Ca(2+) from the medium and dantrolene all served to inhibit calcium elevation and attenuate the activation of CREB. Treatment with an apoE peptide was also found to facilitate transcription of the CREB-dependent genes, c-fos and Bcl-2. In contrast to treatment with apoE3, our findings suggest apoE4 and apoE-peptide induce a novel signaling pathway.

Full Text

Duke Authors

Cited Authors

  • Ohkubo, N; Mitsuda, N; Tamatani, M; Yamaguchi, A; Lee, YD; Ogihara, T; Vitek, MP; Tohyama, M

Published Date

  • February 2001

Published In

Volume / Issue

  • 276 / 5

Start / End Page

  • 3046 - 3053

PubMed ID

  • 11042199

Pubmed Central ID

  • 11042199

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.m005070200

Language

  • eng