ApoE protects cortical neurones against neurotoxicity induced by the non-fibrillar C-terminal domain of the amyloid-beta peptide

J Neurochem. 2001 Jan;76(1):117-27. doi: 10.1046/j.1471-4159.2001.00047.x.

Abstract

Although the genetic link between the epsilon 4 allele of apolipoprotein E (apoE) and Alzheimer's disease (AD) is well established, the apoE isoform-specific activity underlying this correlation remains unclear. We have recently characterized the interaction of the soluble the amyloid-beta peptide (A beta) with model membrane and demonstrated that non-fibrillar A beta peptide, including N-terminal truncated forms of A beta, induced apoptotic cell death in primary rat cortical neurones in vitro. To further investigate the potential interaction between apoE and A beta in the pathogenesis of AD, we have determined the effect of apoE isoforms on the neurotoxicity of non-fibrillar A beta peptides. We demonstrate here that the apoE2 and E3 isoforms protect cortical neurones against apoptotic cell death induced by a non-fibrillar form of the A beta(1-40), A beta(12-42), A beta(29-40) and A beta(29-42) peptides, whereas apoE4 had no effect. This effect involves the formation of stable complexes between apoE and the C-terminal domain (e.g. amino acids 29-40) of A beta(1-40). Interestingly, apoE had no effect on the toxicity induced by aggregated A beta peptides, suggesting a lack of interaction between apoE and amyloid fibrils. Our results provide evidence that interaction with the C-terminal domain of A beta, apoE2 and E3, but not apoE4, inhibits the interactions of the non-fibrillar A beta peptide with the plasma membrane of neurones, A beta peptide aggregation and subsequent neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemical synthesis
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / metabolism*
  • Apolipoproteins E / pharmacology
  • Apoptosis / drug effects
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry
  • Peptide Fragments / toxicity*
  • Protein Binding / drug effects
  • Protein Isoforms / metabolism
  • Protein Isoforms / pharmacology
  • Rats
  • Rats, Wistar

Substances

  • Amyloid beta-Peptides
  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E
  • Peptide Fragments
  • Protein Isoforms
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • amyloid beta-protein (29-40)