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Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin

Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives n...

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Autores principales: Doi, Yukiko, Takeuchi, Hideyuki, Mizoguchi, Hiroyuki, Fukumoto, Kazuya, Horiuchi, Hiroshi, Jin, Shijie, Kawanokuchi, Jun, Parajuli, Bijay, Sonobe, Yoshifumi, Mizuno, Tetsuya, Suzumura, Akio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111597/
https://www.ncbi.nlm.nih.gov/pubmed/25062013
http://dx.doi.org/10.1371/journal.pone.0103458
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author Doi, Yukiko
Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Fukumoto, Kazuya
Horiuchi, Hiroshi
Jin, Shijie
Kawanokuchi, Jun
Parajuli, Bijay
Sonobe, Yoshifumi
Mizuno, Tetsuya
Suzumura, Akio
author_facet Doi, Yukiko
Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Fukumoto, Kazuya
Horiuchi, Hiroshi
Jin, Shijie
Kawanokuchi, Jun
Parajuli, Bijay
Sonobe, Yoshifumi
Mizuno, Tetsuya
Suzumura, Akio
author_sort Doi, Yukiko
collection PubMed
description Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD.
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spelling pubmed-41115972014-07-29 Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin Doi, Yukiko Takeuchi, Hideyuki Mizoguchi, Hiroyuki Fukumoto, Kazuya Horiuchi, Hiroshi Jin, Shijie Kawanokuchi, Jun Parajuli, Bijay Sonobe, Yoshifumi Mizuno, Tetsuya Suzumura, Akio PLoS One Research Article Soluble oligomeric amyloid β (oAβ) causes synaptic dysfunction and neuronal cell death, which are involved in the pathogenesis of Alzheimer's disease (AD). The hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) is expressed in the central nervous system (CNS) and drives neurogenesis. Here we show that G-CSF attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ-degrading enzyme neprilysin (NEP) in neurons, while the NEP inhibitor thiorphan abolished the neuroprotection. Inhibition of MEK5/ERK5, a major downstream effector of G-CSF signaling, also ablated neuroprotective effect of G-CSF. Furthermore, intracerebroventricular administration of G-CSF enhanced NEP enzymatic activity and clearance of Aβ in APP/PS1 transgenic mice. Thus, we propose that G-CSF may be a possible therapeutic strategy against AD. Public Library of Science 2014-07-25 /pmc/articles/PMC4111597/ /pubmed/25062013 http://dx.doi.org/10.1371/journal.pone.0103458 Text en © 2014 Doi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Doi, Yukiko
Takeuchi, Hideyuki
Mizoguchi, Hiroyuki
Fukumoto, Kazuya
Horiuchi, Hiroshi
Jin, Shijie
Kawanokuchi, Jun
Parajuli, Bijay
Sonobe, Yoshifumi
Mizuno, Tetsuya
Suzumura, Akio
Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title_full Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title_fullStr Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title_full_unstemmed Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title_short Granulocyte-Colony Stimulating Factor Attenuates Oligomeric Amyloid β Neurotoxicity by Activation of Neprilysin
title_sort granulocyte-colony stimulating factor attenuates oligomeric amyloid β neurotoxicity by activation of neprilysin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111597/
https://www.ncbi.nlm.nih.gov/pubmed/25062013
http://dx.doi.org/10.1371/journal.pone.0103458
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