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 effect, 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 cells. A dose of 10 microM apoE (141-155)2 resulted in the death of approximately 50% of the neurons within 24 h. Nuclear condensation and DNA fragmentation preceded 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-associated peptide (RAP), an antagonist for apoE receptors, did not protect cells in either SCG or hippocampal cultures. In addition, RAP had no effect on internalization of the apoE peptide. These data support the observation that apoE (141-155)2 is neurotoxic but suggest that the neurotoxicity is distinct from classical apoptosis or necrosis. Furthermore, these results indicate that the toxic effect may occur independently of members of the low-density lipoprotein receptor gene family.
Department of Neurology and Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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Johnson
D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D011188:Potassium / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000502:physiology; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects
D001057:Apolipoproteins E; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D011973:Receptors, LDL; C117630:apolipoprotein E (141-155); D011188:Potassium