Analysis of a novel mechanism of neuronal toxicity produced by an apolipoprotein E-derived peptide

The apolipoprotein E (apoE)-derived peptide (141-155)(2) has a neurotoxic e ffect, implying that apoE itself could be a source of toxicity in Alzheimer 's disease brain. We characterized the toxicity of this peptide on superior cervical ganglion (SCG) neurons and compared the death with the apoptotic death that occurs after nerve growth factor (NGF) deprivation in these cell s. A dose of 10 mu M apoE (141-155)2 resulted in the death of similar to 50 % of the neurons within 24 h, Nuclear condensation and DNA fragmentation pr eceded the death. However, most inhibitors of NGF deprivation-induced death , including the caspase inhibitor Boc-aspartyl(O-methyl)fluoromethyl ketone and genetic deletion of bax(-/-), had no effect on the toxicity. Inclusion of depolarizing levels of potassium did block the toxicity, Receptor-assoc iated peptide (RAP), an antagonist for apoE receptors, did not protect cell s in either SCG or hippocampal cultures. In addition, RAP had no effect on internalization of the apoE peptide. These data support the observation tha t apoE (141-155)(2) is neurotoxic but suggest that the neurotoxicity is dis tinct from classical apoptosis or necrosis. Furthermore, these results indi cate that the toxic effect may occur independently of members of the low-de nsity lipoprotein receptor gene family.