Neuronal cell apoptosis by a receptor-binding domain peptide of ApoE4, notthrough low-density lipoprotein receptor-related protein

Since an apolipoprotein E4 (ApoE4) peptide composed of the low-density lipo protein (LDL) receptor-related protein (LRP)-binding domain [ApoE4(141-149) (2) or ApoE(141-155)(2)] exerts neurotoxicity in primary newtons and neuron al cell lines, it has been controversial whether these effects are mediated by LRP. Here, we examined whether ApoE4(141-149)(2)-induced toxicity is me diated by LRP in a neuronal cell system where ApoE4 toxicity is mediated by LRP: serum-deprived F11 neuronal cells. In these cells, where ApoE4 exerte d toxicity by apoptosis in a manner sensitive to both caspase inhibitors an d pertussis toxin (PTX), ApoE4(141-149)(2) also caused cell death by apopto sis but in a caspase-inhibitor-resistant, PTX-resistant manner. ApoE4(141-1 49)(2)-induced death was not inhibited by antisense oligonucleotides to LRP . Therefore, we conclude that ApoE4(141-149)(2) is able to exert neurotoxic ity without involving LRP. (C) 2000 Academic Press.