Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases.
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.
Hashimoto
Y
Y
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Tokyo 160, Japan.
Jiang
H
H
Niikura
T
T
Ito
Y
Y
Hagiwara
A
A
Umezawa
K
K
Abe
Y
Y
Murayama
Y
Y
Nishimoto
I
I
D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D006822:Hybrid Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D026541:Heymann Nephritis Antigenic Complex; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D000511:alpha-Macroglobulins; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins