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, Y. Abe, Y. Murayama, I. Nishimoto

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77 Citations (Scopus)


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
Issue number22
Publication statusPublished - 2000 Nov 15


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

ASJC Scopus subject areas

  • Neuroscience(all)


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