Neuroprotective effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo

Tomohiro Chiba, Yuichi Hashimoto, Hirohisa Tajima, Marina Yamada, Rikiya Kato, Takako Niikura, Kenzo Terashita, Howard Schulman, Sadakazu Aiso, Yoshiko Kita, Masaaki Matsuoka, Ikuo Nishimoto

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39 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease, affecting mostly middle-aged people. There are no curative therapies for ALS. Several lines of evidence have supported the notion that the proapoptotic property of familial ALS (FALS)-linked mutant Cu/Zn-superoxide dismutase-1 (SOD1) genes may play an important role in the pathogenesis of some FALS cases. Here we found that activity-dependent neurotrophic factor (ADNF), a neurotrophic factor originally identified to have the anti-Alzheimer's disease (AD) activity, protected against neuronal cell death caused by FALS-linked A4T-, G85R- and G93R-SOD1 in a dose-responsive fashion. Notably, ADNF-mediated complete suppression of SOD1 mutant-induced neuronal cell death occurs at concentrations as low as 100 fM. ADNF maintains the neuroprotective activity even at concentrations of more than 1 nM. This is in clear contrast to the previous finding that ADNF loses its protective activity against neurotoxicity induced by AD-relevant insults, including some familial AD genes and amyloid β peptide at concentrations of more than 1 nM. Characterization of the neuroprotective activity of ADNF against cell death caused by SOD1 mutants revealed that CaMKIV and certain tyrosine kinases are involved in ADNF-mediated neuroprotection. Moreover, in vivo studies showed that intracerebroventricularly administered ADNF significantly improved motor performance of G93A-SOD1 transgenic mice, a widely used model of FALS, although survival was extended only marginally. Thus, the neuroprotective activity of ADNF provides a novel insight into the development of curative drugs for ALS.

Original languageEnglish
Pages (from-to)542-552
Number of pages11
JournalJournal of neuroscience research
Volume78
Issue number4
DOIs
Publication statusPublished - 2004 Nov 15

Keywords

  • ADNF
  • ALS
  • Neuronal cell death
  • Neuroprotection
  • SOD1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Chiba, T., Hashimoto, Y., Tajima, H., Yamada, M., Kato, R., Niikura, T., Terashita, K., Schulman, H., Aiso, S., Kita, Y., Matsuoka, M., & Nishimoto, I. (2004). Neuroprotective effect of activity-dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis-linked mutant SOD1 in vitro and in vivo. Journal of neuroscience research, 78(4), 542-552. https://doi.org/10.1002/jnr.20305