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Vol. 300, Issue 3, 736-745, March 2002

Neurotoxic Mechanisms by Alzheimer's Disease-Linked N141I Mutant Presenilin 2

Yuichi Hashimoto, Takako Niikura, Yuko Ito, Yoshiko Kita, Kenzo Terashita and Ikuo Nishimoto

Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo Japan

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 Galpha o, 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.

0022-3565/02/3003-0736$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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