Neurotoxic Mechanisms by Alzheimer's Disease-Linked N141I Mutant Presenilin 2
- Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo Japan
- Dr. Ikuo Nishimoto, Department of Pharmacology and Neurosciences, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail:nisimoto{at}sc.itc.keio.ac.jp
Abstract
Although it has been established that oxidative stress mediates cytotoxicity by familial Alzheimer's disease (FAD)-linked mutants of presenilin (PS)1 and that pertussis toxin inhibits cytotoxicity by FAD-linked N141I-PS2, it has not been determined whether oxidative stress is involved in cytotoxicity by N141I-PS2 or which pertussis toxin-sensitive proteins mediate the cytotoxicity. Here we report that low expression of N141I-PS2 caused neuronal cell death, whereas low expression of wild-type PS2 did not. Cytotoxicities by low and high expression of N141I-PS2 occurred through dissimilar mechanisms: the former cytotoxicity was blocked by a cell-permeable caspase inhibitor, and the latter was not. Since both mechanisms were sensitive to a cell-permeable antioxidant, we examined potential sources of reactive oxygen species in each mechanism, and found that the caspase inhibitor-sensitive neurotoxicity by N141I-PS2 was likely through NADPH oxidase and the caspase inhibitor-resistant neurotoxicity by N141I-PS2 through xanthine oxidase. Pertussis toxin greatly suppressed both toxic mechanisms by N141I-PS2, and only Gαo, a neuron-enriched pertussis toxin-sensitive G protein, was involved in both mechanisms. We therefore conclude that N141I-PS2 is capable of triggering multiple neurotoxic mechanisms, which can be inhibited by the combination of clinically usable inhibitors of NADPH oxidase and xanthine oxidase. This study thus provides a novel insight into the therapeutic intervention of PS2 mutant-associated FAD.
Footnotes
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This work was supported in part by grants from Tomy Medico, Noevir, Japan Foundation for Neuroscience and Mental Health (Y. H.), Ono Medical Research Foundation, Keio Gijuku Academic Development Funds (Y. H. and Y. K.), and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
- Abbreviations:
- FAD
- familial Alzheimer's disease
- PS
- presenilin
- APP
- amyloid precursor protein
- NL-APP
- K595N/M596L-APP
- PTX
- pertussis toxin
- GEE
- glutathione-ethyl-ester
- DEVD
- Ac-DEVD-CHO
- APO
- apocynin
- DPI
- diphenyleneiodonium
- XO
- xanthine oxidase
- XOI
- XO inhibitor
- ROS
- reactive oxygen species
- OXYP
- oxypurinol
- CTF
- C-terminal fragment
- EGFP
- enhanced green fluorescent protein
- wt
- wild-type
- FBS
- fetal bovine serum
- EcD
- ecdysone
- EtOH
- ethanol
- PTXr-Gα
- PTX-resistant mutant of G protein α subunit Gαi1, Gαi2, Gαi3, or Gαo
- l-NAME
- Nω-nitro-l-arginine methyl ester
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- Received August 20, 2001.
- Accepted November 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
