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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2011

Open Access 01-12-2011 | Research article

Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons

Authors: Cha-Gyun Jung, Kyung-Ok Uhm, Yutaka Miura, Takashi Hosono, Hirofumi Horike, Kum Kum Khanna, Mi-Jeong Kim, Makoto Michikawa

Published in: Molecular Neurodegeneration | Issue 1/2011

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Abstract

Background

Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown.

Results

We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM.

Conclusions

To the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD.
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Metadata
Title
Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons
Authors
Cha-Gyun Jung
Kyung-Ok Uhm
Yutaka Miura
Takashi Hosono
Hirofumi Horike
Kum Kum Khanna
Mi-Jeong Kim
Makoto Michikawa
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2011
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-6-47

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