Neuronal cell apoptosis by a receptor-binding domain peptide of ApoE4, not through low-density lipoprotein receptor-related protein.
Since an apolipoprotein E4 (ApoE4) peptide composed of the low-density lipoprotein (LDL) receptor-related protein (LRP)-binding domain [ApoE4(141-149)(2) or ApoE(141-155)(2)] exerts neurotoxicity in primary neurons and neuronal cell lines, it has been controversial whether these effects are mediated by LRP. Here, we examined whether ApoE4(141-149)(2)-induced toxicity is mediated by LRP in a neuronal cell system where ApoE4 toxicity is mediated by LRP: serum-deprived F11 neuronal cells. In these cells, where ApoE4 exerted toxicity by apoptosis in a manner sensitive to both caspase inhibitors and pertussis toxin (PTX), ApoE4(141-149)(2) also caused cell death by apoptosis but in a caspase-inhibitor-resistant, PTX-resistant manner. ApoE4(141-149)(2)-induced death was not inhibited by antisense oligonucleotides to LRP. Therefore, we conclude that ApoE4(141-149)(2) is able to exert neurotoxicity without involving LRP.
Hagiwara
A
A
Department of Applied Chemistry, Keio University, Yokohama, Japan.
Hashimoto
Y
Y
Niikura
T
T
Ito
Y
Y
Terashita
K
K
Kita
Y
Y
Nishimoto
I
I
Umezawa
K
K
D000595:Amino Acid Sequence; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001665:Binding Sites; D061945:Caspase Inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D011994:Recombinant Proteins