Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway.
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.
Ohkubo
N
N
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Mitsuda
N
N
Tamatani
M
M
Yamaguchi
A
A
Lee
Y D
YD
Ogihara
T
T
Vitek
M P
MP
Tohyama
M
M
D000818:Animals; D000943:Antigens, Differentiation; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006624:Hippocampus / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D019014:fas Receptor
D000943:Antigens, Differentiation; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D019006:Neural Cell Adhesion Molecules; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D019014:fas Receptor; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium