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

J Neurosci. 2000 Nov 15;20(22):8401-9. doi: 10.1523/JNEUROSCI.20-22-08401.2000.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein E4
  • Apolipoproteins E / antagonists & inhibitors
  • Apolipoproteins E / metabolism*
  • Apolipoproteins E / pharmacology
  • Apoptosis* / drug effects
  • CHO Cells
  • Cell Line
  • Cell Survival / drug effects
  • Cricetinae
  • Dose-Response Relationship, Drug
  • GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Glioblastoma
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Heymann Nephritis Antigenic Complex
  • Humans
  • Hybrid Cells / cytology
  • Hybrid Cells / drug effects
  • Hybrid Cells / metabolism
  • In Situ Nick-End Labeling
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Neuroblastoma
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • Pertussis Toxin
  • Rats
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / metabolism*
  • Receptors, LDL / metabolism
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Transfection
  • Virulence Factors, Bordetella / pharmacology
  • alpha-Macroglobulins / metabolism
  • alpha-Macroglobulins / pharmacology

Substances

  • Apolipoprotein E4
  • Apolipoproteins E
  • Heymann Nephritis Antigenic Complex
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Membrane Glycoproteins
  • Oligonucleotides, Antisense
  • Receptors, Immunologic
  • Receptors, LDL
  • Recombinant Proteins
  • Virulence Factors, Bordetella
  • alpha-Macroglobulins
  • Pertussis Toxin
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Heterotrimeric GTP-Binding Proteins