Neurotoxic mechanisms by Alzheimer's disease-linked N141I mutant presenilin 2.
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.
Hashimoto
Yuichi
Y
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo Japan.
Niikura
Takako
T
Ito
Yuko
Y
Kita
Yoshiko
Y
Terashita
Kenzo
K
Nishimoto
Ikuo
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004440:Ecdysone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006822:Hybrid Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000633:toxicity*; D051379:Mice; D009154:Mutation / Q000502:physiology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000235:genetics* / Q000633:toxicity*; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin; D053766:Presenilin-2; D051381:Rats; D011994:Recombinant Proteins / Q000633:toxicity; D010566:Virulence Factors, Bordetella / Q000633:toxicity; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009498:Neurotoxins; D009842:Oligopeptides; D053766:Presenilin-2; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D004440:Ecdysone; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D037342:Pertussis Toxin; D005978:Glutathione