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Neuroprotective effect of activity‐dependent neurotrophic factor against toxicity from familial amyotrophic lateral sclerosis‐linked mutant SOD1 in vitro and in vivo
Author(s) -
Chiba Tomohiro,
Hashimoto Yuichi,
Tajima Hirohisa,
Yamada Marina,
Kato Rikiya,
Niikura Takako,
Terashita Kenzo,
Schulman Howard,
Aiso Sadakazu,
Kita Yoshiko,
Matsuoka Masaaki,
Nishimoto Ikuo
Publication year - 2004
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20305
Subject(s) - amyotrophic lateral sclerosis , neuroprotection , sod1 , in vivo , neurotrophic factors , toxicity , in vitro , neuroscience , ciliary neurotrophic factor , brain derived neurotrophic factor , pharmacology , mutant , chemistry , medicine , biology , genetics , biochemistry , disease , receptor , gene
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. © 2004 Wiley‐Liss, Inc.