Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases

Y. Hashimoto, H. Jiang, T. Niikura, Y. Ito, A. Hagiwara, K. Umezawa, Yoichiro Abe, Y. Murayama, I. Nishimoto

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Abstract

The ε4 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 μg/ml ApoE4, but not by 30 μg/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, α2-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 Gα(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.

Original languageEnglish
Pages (from-to)8401-8409
Number of pages9
JournalJournal of Neuroscience
Volume20
Issue number22
Publication statusPublished - 2000 Nov 15

Fingerprint

LDL-Receptor Related Proteins
Apolipoprotein E4
LDL Receptors
GTP Phosphohydrolases
Apoptosis
Lipoprotein Receptors
Pertussis Toxin
Proteins
Neuroblastoma
Alzheimer Disease
Apolipoprotein E3
Macroglobulins
Hybrid Cells
Antisense Oligonucleotides
Glioblastoma
Cricetulus
Causality
Transfection

Keywords

  • Alzheimer's disease
  • Apolipoprotein E
  • G-proteins
  • Isoform-specific action
  • Lipoprotein receptor-related protein
  • Neuronal apoptosis
  • Pertussis toxin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hashimoto, Y., Jiang, H., Niikura, T., Ito, Y., Hagiwara, A., Umezawa, K., ... Nishimoto, I. (2000). Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. Journal of Neuroscience, 20(22), 8401-8409.

Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. / Hashimoto, Y.; Jiang, H.; Niikura, T.; Ito, Y.; Hagiwara, A.; Umezawa, K.; Abe, Yoichiro; Murayama, Y.; Nishimoto, I.

In: Journal of Neuroscience, Vol. 20, No. 22, 15.11.2000, p. 8401-8409.

Research output: Contribution to journalArticle

Hashimoto, Y, Jiang, H, Niikura, T, Ito, Y, Hagiwara, A, Umezawa, K, Abe, Y, Murayama, Y & Nishimoto, I 2000, 'Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases', Journal of Neuroscience, vol. 20, no. 22, pp. 8401-8409.
Hashimoto Y, Jiang H, Niikura T, Ito Y, Hagiwara A, Umezawa K et al. Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. Journal of Neuroscience. 2000 Nov 15;20(22):8401-8409.
Hashimoto, Y. ; Jiang, H. ; Niikura, T. ; Ito, Y. ; Hagiwara, A. ; Umezawa, K. ; Abe, Yoichiro ; Murayama, Y. ; Nishimoto, I. / Neuronal apoptosis by apolipoprotein E4 through low-density lipoprotein receptor-related protein and heterotrimeric GTPases. In: Journal of Neuroscience. 2000 ; Vol. 20, No. 22. pp. 8401-8409.
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AU - Hagiwara, A.

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AB - The ε4 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 μg/ml ApoE4, but not by 30 μg/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, α2-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 Gα(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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