Neuronal Apoptosis by Apolipoprotein E4 through Low-Density Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases

作者: Yuichi Hashimoto , Hong Jiang , Takako Niikura , Yuko Ito , Akari Hagiwara

DOI: 10.1523/JNEUROSCI.20-22-08401.2000

关键词: GTPasePertussis toxinMolecular biologyTransfectionChinese hamster ovary cellBiologyHeterotrimeric G proteinG proteinLipoprotein receptor-related proteinApolipoprotein ECell biology

摘要: The epsilon4 genotype of apolipoprotein E (apoE4) is the most established predisposing factor in Alzheimer's disease (AD); however, it remains unclear how apoE4 contributes to pathophysiology. Here, we report that protein (ApoE4) evokes apoptosis neuronal cells through low-density lipoprotein receptor-related (LRP) and heterotrimeric GTPases. We examined neuron/neuroblastoma hybrid F11 found these were killed by 30 microg/ml ApoE4, but not ApoE3. ApoE4-induced death occurred with typical features for time- dose-dependent manners, was observed SH-SY5Y neuroblastomas, glioblastomas or non-neuronal Chinese hamster ovary cells. Activated, native, alpha2-macroglobulin suppressed this ApoE4 toxicity. Suppression antisense oligonucleotide LRP inhibition low nanomolar concentrations LRP-associated RAP provided evidence involvement LRP. GTPases demonstrated findings (1) pertussis toxin (PTX), heat-inactivated PTX; (2) transfection PTX-resistant mutant cDNAs Galpha(i) restored toxicity restricted PTX. thus conclude one neurotoxic mechanisms triggered activate a cell type-specific apoptogenic program involving G(i) class gene may play direct role pathogenesis AD other forms dementia.

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