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

Ohkubo, N; Mitsuda, N; Tamatani, M; Yamaguchi, A; Lee, YD; Ogihara, T; Vitek, MP; Tohyama, M
The Journal of biological chemistry, 276(5):3046-3053, 2001
Journal Title
The Journal of biological chemistry
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.
MeSH terms
AnimalsAntigens, CD95Antigens, Differentiation*Apolipoprotein E3Apolipoprotein E4Apolipoproteins E/geneticsApolipoproteins E/metabolismApolipoproteins E/physiology*Calcium/metabolismCalcium Channels, L-Type/metabolismCyclic AMP Response Element-Binding Protein/geneticsCyclic AMP Response Element-Binding Protein/metabolism*Cyclic AMP-Dependent Protein Kinases/metabolismEnzyme ActivationHippocampus/metabolismLDL-Receptor Related Protein 1Membrane GlycoproteinsMitogen-Activated Protein Kinases/metabolismNeural Cell Adhesion Molecule L1*Neural Cell Adhesion MoleculesNeurons/metabolismPhosphorylationProtein-Serine-Threonine Kinases/metabolismProto-Oncogene Proteins c-bcl-2/biosynthesisProto-Oncogene Proteins c-fos/biosynthesisRatsReceptors, Immunologic*Receptors, Lipoprotein/metabolismReceptors, N-Methyl-D-Aspartate/metabolismRecombinant Proteins/metabolismSerine/metabolismTranscriptional Activation/physiology*
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