Amino- and Carboxyl-Terminal Mutants of Presenilin 1 Cause Neuronal Cell Death Through Distinct Toxic Mechanisms: Study of 27 Different Presenilin 1 Mutants

Yuichi Hashimoto, Emi Tsukamoto, Takako Niikura, Yohichi Yamagishi, Miho Ishizaka, Sadakazu Aiso, Akihiko Takashima, Ikuo Nishimoto

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Presenilin (PS)1 and its mutants, which consist of the N-terminal and C-terminal fragments, cause certain familial forms of Alzheimer's disease (FAD). Our earlier studies found that FAD-linked M146L-PS1 causes neuronal cell death through nitrogen oxide synthase (NOS) and that FAD-linked N141I-PS2, another member of the PS family, causes neuronal cell death through NADPH oxidase. In this study, we examined 27 different FAD-linked mutants of PS1, and found that PS1 mutants with mutations in the N-terminal fragment caused NOS inhibitor (NOSI)-sensitive neuronal cell death; in contrast, the PS1 mutants with mutations in the C-terminal fragment caused NOSI-resistant neuronal cell death. The former toxicity was resistant to the specific NADPH oxidase inhibitor apocynin and was inhibited by Humanin (HN), a newly identified neuroprotective factor against Alzheimer's disease (AD)-relevant insults, but not by insulin-like growth factor-I (IGF-I). In contrast, the latter toxicity was sensitive to apocynin and inhibited by both IGF-I and HN. This study indicates for the first time that N- and C-terminal fragment PS1 mutants can generate distinct neurotoxic signals, which will provide an important clue to the understanding of the entire array of neurotoxic signals generated by FAD-causative mutations of PS1.

Original languageEnglish
Pages (from-to)417-428
Number of pages12
JournalJournal of Neuroscience Research
Volume75
Issue number3
DOIs
Publication statusPublished - 2004 Feb 1

Keywords

  • Alzheimer's disease
  • Humanin
  • IGF-I
  • NADPH oxidase
  • NOS

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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