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J. Biol. Chem., Vol. 275, Issue 44, 34541-34551, November 3, 2000
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From the Departments of Pharmacology and Neurosciences, KEIO
University School of Medicine, Shinanomachi, Tokyo 160, Japan
We examined a neuronal cell system in which
single-cell expression of either familial Alzheimer's disease (FAD)
gene V642I-APP or K595N/M596L-APP (NL-APP) in an inducible plasmid was
controlled without affecting transfection efficiency. This system
revealed that (i) low expression of both mutants exerted toxicity
sensitive to both Ac-DEVD-CHO (DEVD) and glutathione ethyl ester (GEE), whereas wild-type APP (wtAPP) only at higher expression levels caused
GEE/DEVD-resistant death to lesser degrees; (ii) toxicity by the V642I
mutation was entirely GEE/DEVD sensitive; and (iii) toxicity by higher
expression of NL-APP was GEE/DEVD resistant. The GEE/DEVD-sensitive
death was sensitive to pertussis toxin and was due to
Go-interacting
His657-Lys676 domain. The
GEE/DEVD-resistant death was due to C-terminal
Met677-Asn695. APP mutants lacking either
domain unraveled elaborate intracellular cross-talk between these
domains. E618Q-APP, responsible for non-AD type of a human disease,
only exerted GEE/DEVD-resistant death at higher expression. Therefore,
(i) different FAD mutations in APP cause neuronal cell death through
different cytoplasmic domains via different sets of mechanisms; (ii)
expression levels of FAD genes are critical in activating specific
death mechanisms; and (iii) toxicity by low expression of both mutants
most likely reflects the pathogenetic mechanism of FAD.
Multiple Mechanisms Underlie Neurotoxicity by Different Types of
Alzheimer's Disease Mutations of Amyloid Precursor Protein*
,
*
This work was supported in part by grants from Naito
Foundation, Brain Science Foundation, Takeda Medical Research
Foundation, Takeda Science Foundation, the Ministry of Health and
Welfare of Japan, the Ministry of Education, Science, and Culture of
Japan and the Organization for Pharmaceutical Safety and Research
(OPSR).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 81-3-3359-8909;
Fax: 81-3-5363-8428; E-mail: nisimoto@mc.med.keio.ac.jp or
niikurat@med.keio.ac.jp.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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