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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2000-11-14
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pubmed:abstractText |
The epsilon4 genotype of apolipoprotein E (apoE4) is the most established predisposing factor in Alzheimer's disease (AD); however, it remains unclear how apoE4 contributes to the pathophysiology. Here, we report that the apoE4 protein (ApoE4) evokes apoptosis in neuronal cells through the low-density lipoprotein receptor-related protein (LRP) and heterotrimeric GTPases. We examined neuron/neuroblastoma hybrid F11 cells and found that these cells were killed by 30 microg/ml ApoE4, but not by 30 microg/ml ApoE3. ApoE4-induced death occurred with typical features for apoptosis in time- and dose-dependent manners, and was observed in SH-SY5Y neuroblastomas, but not in glioblastomas or non-neuronal Chinese hamster ovary cells. Activated, but not native, alpha2-macroglobulin suppressed this ApoE4 toxicity. Suppression by the antisense oligonucleotide to LRP and inhibition by low nanomolar concentrations of LRP-associated protein RAP provided evidence for the involvement of LRP. The involvement of heterotrimeric GTPases was demonstrated by the findings that (1) ApoE4-induced death was suppressed by pertussis toxin (PTX), but not by heat-inactivated PTX; and (2) transfection with PTX-resistant mutant cDNAs of Galpha(i) restored the toxicity of ApoE4 restricted by PTX. We thus conclude that one of the neurotoxic mechanisms triggered by ApoE4 is to activate a cell type-specific apoptogenic program involving LRP and the G(i) class of GTPases and that the apoE4 gene may play a direct role in the pathogenesis of AD and other forms of dementia.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Apolipoprotein E4,
http://linkedlifedata.com/resource/pubmed/chemical/Apolipoproteins E,
http://linkedlifedata.com/resource/pubmed/chemical/GTP-Binding Protein alpha...,
http://linkedlifedata.com/resource/pubmed/chemical/Heterotrimeric GTP-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Heymann Nephritis Antigenic Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Low Density Lipoprotein...,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, Antisense,
http://linkedlifedata.com/resource/pubmed/chemical/Pertussis Toxin,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Immunologic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Virulence Factors, Bordetella,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-Macroglobulins
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1529-2401
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
20
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8401-9
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:11069947-Animals,
pubmed-meshheading:11069947-Apolipoprotein E4,
pubmed-meshheading:11069947-Apolipoproteins E,
pubmed-meshheading:11069947-Apoptosis,
pubmed-meshheading:11069947-CHO Cells,
pubmed-meshheading:11069947-Cell Line,
pubmed-meshheading:11069947-Cell Survival,
pubmed-meshheading:11069947-Cricetinae,
pubmed-meshheading:11069947-Dose-Response Relationship, Drug,
pubmed-meshheading:11069947-GTP-Binding Protein alpha Subunits, Gi-Go,
pubmed-meshheading:11069947-Glioblastoma,
pubmed-meshheading:11069947-Heterotrimeric GTP-Binding Proteins,
pubmed-meshheading:11069947-Heymann Nephritis Antigenic Complex,
pubmed-meshheading:11069947-Humans,
pubmed-meshheading:11069947-Hybrid Cells,
pubmed-meshheading:11069947-In Situ Nick-End Labeling,
pubmed-meshheading:11069947-Low Density Lipoprotein Receptor-Related Protein-1,
pubmed-meshheading:11069947-Membrane Glycoproteins,
pubmed-meshheading:11069947-Mice,
pubmed-meshheading:11069947-Neuroblastoma,
pubmed-meshheading:11069947-Neurons,
pubmed-meshheading:11069947-Oligonucleotides, Antisense,
pubmed-meshheading:11069947-Pertussis Toxin,
pubmed-meshheading:11069947-Rats,
pubmed-meshheading:11069947-Receptors, Immunologic,
pubmed-meshheading:11069947-Receptors, LDL,
pubmed-meshheading:11069947-Recombinant Proteins,
pubmed-meshheading:11069947-Transfection,
pubmed-meshheading:11069947-Virulence Factors, Bordetella,
pubmed-meshheading:11069947-alpha-Macroglobulins
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pubmed:year |
2000
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pubmed:articleTitle |
Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases.
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pubmed:affiliation |
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Tokyo 160, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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