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

Although the genetic link between the epsilon4 allele of apolipoprotein E ( apoE) and Alzheimer's disease (AD) is well established, the apoE isoform-sp ecific activity underlying this correlation remains unclear. We have recent ly characterized the interaction of the soluble the amyloid-beta peptide (A beta) with model membrane and demonstrated that non-fibrillar A beta pepti de, 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, w e have determined the effect of apoE isoforms on the neurotoxicity of non-f ibrillar A beta peptides. We demonstrate here that the apoE2 and E3 isoform s protect cortical neurones against apoptotic cell death induced by a non-f ibrillar form of the A beta (1-40), A beta (12-42), A beta (29-40) and A be ta (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 th e toxicity induced by aggregated A beta peptides, suggesting a lack of inte raction between apoE and amyloid fibrils. Our results provide evidence that interaction with the C-terminal domain of A beta, apoE2 and E3, but not ap oE4, inhibits the interactions of the non-fibrillar A beta peptide with the plasma membrane of neurones, A beta peptide aggregation and subsequent neu rotoxicity.