Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

Katja Kanninen; Tarja M. Malm; Henna Kaisa Jyrkkänen; Gundars Goldsteins; Velta Keksa-Goldsteine; Heikki Tanila; Masayuki Yamamoto; Seppo Ylä-Herttuala; Anna Liisa Levonen; Jari Koistinaho

doi:10.1016/j.mcn.2008.07.010

Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

Katja Kanninen, Tarja M. Malm, Henna Kaisa Jyrkkänen, Gundars Goldsteins, Velta Keksa-Goldsteine, Heikki Tanila, Masayuki Yamamoto, Seppo Ylä-Herttuala, Anna Liisa Levonen, Jari Koistinaho

Tohoku Medical Megabank Organization (ToMMo)

University of Eastern Finland

Research output: Contribution to journal › Article › peer-review

205 Citations (Scopus)

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Aβ). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Aβ deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Aβ toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.

Original language	English
Pages (from-to)	302-313
Number of pages	12
Journal	Molecular and Cellular Neurosciences
Volume	39
Issue number	3
DOIs	https://doi.org/10.1016/j.mcn.2008.07.010
Publication status	Published - 2008 Oct 29

Keywords

Gene transfer
Knock-out
Neuroprotection
Oxidative stress
Transgenic

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10.1016/j.mcn.2008.07.010

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title = "Nuclear factor erythroid 2-related factor 2 protects against beta amyloid",

abstract = "Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Aβ). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Aβ deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Aβ toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.",

keywords = "Gene transfer, Knock-out, Neuroprotection, Oxidative stress, Transgenic",

author = "Katja Kanninen and Malm, {Tarja M.} and Jyrkk{\"a}nen, {Henna Kaisa} and Gundars Goldsteins and Velta Keksa-Goldsteine and Heikki Tanila and Masayuki Yamamoto and Seppo Yl{\"a}-Herttuala and Levonen, {Anna Liisa} and Jari Koistinaho",

note = "Funding Information: We thank Laila Kaskela, Mirka Tikkanen, Anne Martikainen, Sari J{\"a}rvel{\"a}inen, Tiina Koponen and Lakshman Puli for their expert technical assistance. This work was supported by Finland's Academy (J.K. and A.L.L.), Sigrid Juselius Foundation (J.K. and A.L.L.), the Institute for the study of Aging (J.K.) and the Nordic Centre of Excellence Program in Molecular Medicine 2004–2009 entitled “Neurodegeneration” (J.K.).",

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doi = "10.1016/j.mcn.2008.07.010",

language = "English",

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journal = "Molecular and Cellular Neurosciences",

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T1 - Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

AU - Kanninen, Katja

AU - Malm, Tarja M.

AU - Jyrkkänen, Henna Kaisa

AU - Goldsteins, Gundars

AU - Keksa-Goldsteine, Velta

AU - Tanila, Heikki

AU - Yamamoto, Masayuki

AU - Ylä-Herttuala, Seppo

AU - Levonen, Anna Liisa

AU - Koistinaho, Jari

N1 - Funding Information: We thank Laila Kaskela, Mirka Tikkanen, Anne Martikainen, Sari Järveläinen, Tiina Koponen and Lakshman Puli for their expert technical assistance. This work was supported by Finland's Academy (J.K. and A.L.L.), Sigrid Juselius Foundation (J.K. and A.L.L.), the Institute for the study of Aging (J.K.) and the Nordic Centre of Excellence Program in Molecular Medicine 2004–2009 entitled “Neurodegeneration” (J.K.).

PY - 2008/10/29

Y1 - 2008/10/29

N2 - Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Aβ). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Aβ deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Aβ toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.

AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the up-regulation of cytoprotective genes via the antioxidant response element (ARE). In the pathogenesis of Alzheimer's disease (AD) current evidence supports the role of oxidative stress. Considering the protective role of Nrf2 against oxidative injury, we studied Nrf2 and Nrf2-ARE target genes in transgenic AD mice and tested whether Nrf2 could confer neuroprotection against amyloid-beta peptides (Aβ). Nrf2-ARE pathway was attenuated in APP/PS1 transgenic mouse brain at the time of Aβ deposition. Boosting the activity of the Nrf2-ARE pathway by tert-butylhydroquinone treatment or adenoviral Nrf2 gene transfer protected against Aβ toxicity. This neuroprotection was associated with increased expression of Nrf2 target genes and reduced phosphorylation of p66Shc, a marker of increased susceptibility for oxidative stress. The findings suggest that the Nrf2-ARE pathway may be impaired in AD and that induction of the Nrf2-ARE defence mechanism may prevent or delay AD-like pathology.

KW - Gene transfer

KW - Knock-out

KW - Neuroprotection

KW - Oxidative stress

KW - Transgenic

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JO - Molecular and Cellular Neurosciences

JF - Molecular and Cellular Neurosciences

IS - 3

ER -

Nuclear factor erythroid 2-related factor 2 protects against beta amyloid

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Keywords

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