Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant

Yoichiro Abe, Yuichi Hashimoto, Yusuke Tomita, Kenzo Terashita, Sadakazu Aiso, Hirohisa Tajima, Takako Niikura, Masaaki Matsuoka, Ikuo Nishimoto

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Although neurotoxic functions are well characterized in familial Alzheimer's disease (FAD)-linked N141I mutant of presenilin (PS)2, little has been known about M239V-PS2, another established FAD-causative mutant. We found that expression of M239V-PS2 caused neuronal cytotoxicity. M239V-PS2 exerted three forms of cytotoxicity: one was sensitive to both an antioxidant glutathione-ethyl-ester (GEE) and a caspase inhibitor Ac-DEVD-CHO (DEVD); the second was sensitive to GEE but resistant to DEVD; and the third was resistant to both. The GEE/DEVD-sensitive cytotoxicity by M239V-PS2 was likely through NADPH oxidase and the GEE-sensitive/DEVD-resistant cytotoxicity through xanthine oxidase (XO). Both mechanisms by M239V-PS2 were suppressed by pertussis toxin (PTX) and were mediated by Gαo, but not by Gα i. Although Aβ1-43 itself induced no cytotoxicity, Aβ1-43 potentiated all three components of M239V-PS2 cytotoxicity. As these cytotoxic mechanisms by M239V-PS2 are fully shared with N141I-PS2, they are most likely implicated in the pathomechanism of FAD by PS2 mutations. Notably, cytotoxicity by M239V-PS2 could be inhibited by the combination of two clinically usable inhibitors of superoxide-generating enzymes, apocynin and oxypurinol.

Original languageEnglish
Pages (from-to)583-595
Number of pages13
JournalJournal of neuroscience research
Issue number4
Publication statusPublished - 2004 Aug 15


  • G protein
  • Humanin
  • NADPH oxidase
  • Neuronal cell death
  • Presenilin 2
  • Xanthine oxidase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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