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 journalArticle

11 Citations (Scopus)

Abstract

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
Volume77
Issue number4
DOIs
Publication statusPublished - 2004 Aug 15
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant. / Abe, Yoichiro; Hashimoto, Yuichi; Tomita, Yusuke; Terashita, Kenzo; Aiso, Sadakazu; Tajima, Hirohisa; Niikura, Takako; Matsuoka, Masaaki; Nishimoto, Ikuo.

In: Journal of Neuroscience Research, Vol. 77, No. 4, 15.08.2004, p. 583-595.

Research output: Contribution to journalArticle

Abe, Y, Hashimoto, Y, Tomita, Y, Terashita, K, Aiso, S, Tajima, H, Niikura, T, Matsuoka, M & Nishimoto, I 2004, 'Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant', Journal of Neuroscience Research, vol. 77, no. 4, pp. 583-595. https://doi.org/10.1002/jnr.20163
Abe, Yoichiro ; Hashimoto, Yuichi ; Tomita, Yusuke ; Terashita, Kenzo ; Aiso, Sadakazu ; Tajima, Hirohisa ; Niikura, Takako ; Matsuoka, Masaaki ; Nishimoto, Ikuo. / Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant. In: Journal of Neuroscience Research. 2004 ; Vol. 77, No. 4. pp. 583-595.
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