Multiple pathways of apolipoprotein E signaling in primary neurons.
Apolipoprotein E is a genetic risk factor for Alzheimer's disease, and the apoE protein is associated with beta-amyloid deposits in Alzheimer's disease brain. We examined signaling pathways stimulated by apoE in primary neurons in culture. ApoE and an apoE-derived peptide activated several intracellular kinases, including prominently extracellular signal-regulated kinase 1/2 (ERK1/2). ERK1/2 activation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family, the specific NMDA glutamate receptor antagonist MK 801 and other calcium channel blockers. Activation of apoE receptors also induced tyrosine phosphorylation of Dab1, an adaptor protein of apoE receptors, but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for ERK activation. In contrast, apoE treatment of primary neurons decreased activation of c-Jun N-terminal kinase, a kinase that interacts with another apoE receptor adaptor protein, c-Jun N-terminal kinase-interacting protein. This change also depended on interactions with the low-density lipoprotein receptor family but was independent of calcium channels. c-Jun N-terminal kinase deactivation by apoE was blocked by gamma-secretase inhibitors and pertussis toxin. These results demonstrate that apoE affects several signaling cascades in neurons: increased disabled phosphorylation, activation of the ERK1/2 pathway (dependent on calcium influx via the NMDA receptor) and inhibition of the c-Jun N-terminal kinase 1/2 pathway (dependent on gamma-secretase and G proteins).
Hoe
Hyang-Sook
HS
Department of Neuroscience, Georgetown University, Washington, DC 20057-1464, USA.
Harris
D Christopher
DC
Rebeck
G William
GW
D000704:Analysis of Variance; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D000077191:Wortmannin; D019061:src-Family Kinases / Q000378:metabolism
D000730:Androstadienes; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D016291:Dizocilpine Maleate; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines; D000077191:Wortmannin; D019061:src-Family Kinases; C103773:Dab1 protein, mouse; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one