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The Journal of Neuroscience, November 15, 2000, 20(22):8401-8409
Neuronal Apoptosis by Apolipoprotein E4 through Low-Density
Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases
Yuichi
Hashimoto1,
Hong
Jiang1,
Takako
Niikura1,
Yuko
Ito1,
Akari
Hagiwara2,
Kazuo
Umezawa2,
Yoichiro
Abe1,
Yoshitake
Murayama3, and
Ikuo
Nishimoto1
1 Department of Pharmacology and Neurosciences,
KEIO University School of Medicine, Shinanomachi, Tokyo 160, Japan, 2 Department of Applied Chemistry, Faculty of
Science and Technology, KEIO University, Yokohama 223, Japan, and
3 Fourth Department of Medicine, University of Tokyo
School of Medicine, Mejirodai, Tokyo 113, Japan
The  4 genotype of apolipoprotein E (apoE4) is the most
established predisposing factor in Alzheimer's disease (AD); however, it remains unclear how apoE4 contributes to the pathophysiology. Here,
we report that the apoE4 protein (ApoE4) evokes apoptosis in neuronal
cells through the low-density lipoprotein receptor-related protein (LRP) and heterotrimeric GTPases. We examined
neuron/neuroblastoma hybrid F11 cells and found that these cells were
killed by 30 µg/ml ApoE4, but not by 30 µg/ml ApoE3. ApoE4-induced
death occurred with typical features for apoptosis in time- and
dose-dependent manners, and was observed in SH-SY5Y neuroblastomas, but
not in glioblastomas or non-neuronal Chinese hamster ovary
cells. Activated, but not native,  2-macroglobulin suppressed this
ApoE4 toxicity. Suppression by the antisense oligonucleotide to LRP and
inhibition by low nanomolar concentrations of LRP-associated protein
RAP provided evidence for the involvement of LRP. The
involvement of heterotrimeric GTPases was demonstrated by the findings
that (1) ApoE4-induced death was suppressed by pertussis toxin (PTX), but not by heat-inactivated PTX; and (2) transfection with
PTX-resistant mutant cDNAs of Gi restored the toxicity
of ApoE4 restricted by PTX. We thus conclude that one of the neurotoxic
mechanisms triggered by ApoE4 is to activate a cell type-specific
apoptogenic program involving LRP and the Gi class of
GTPases and that the apoE4 gene may play a direct role in the
pathogenesis of AD and other forms of dementia.
Key words:
apolipoprotein E; isoform-specific action; neuronal
apoptosis; lipoprotein receptor-related protein; G-proteins; pertussis
toxin; Alzheimer's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20228401-09$05.00/0
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