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Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture

Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated micro...

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Autores principales: Garwood, C J, Pooler, A M, Atherton, J, Hanger, D P, Noble, W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168992/
https://www.ncbi.nlm.nih.gov/pubmed/21633390
http://dx.doi.org/10.1038/cddis.2011.50
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author Garwood, C J
Pooler, A M
Atherton, J
Hanger, D P
Noble, W
author_facet Garwood, C J
Pooler, A M
Atherton, J
Hanger, D P
Noble, W
author_sort Garwood, C J
collection PubMed
description Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aβ-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aβ-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aβ-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aβ-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aβ in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy.
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spelling pubmed-31689922011-09-20 Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture Garwood, C J Pooler, A M Atherton, J Hanger, D P Noble, W Cell Death Dis Original Article Alzheimer's disease (AD) is pathologically characterised by the age-dependent deposition of β-amyloid (Aβ) in senile plaques, intraneuronal accumulation of tau as neurofibrillary tangles, synaptic dysfunction and neuronal death. Neuroinflammation, typified by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of AD. We have used primary rat neuronal, astrocytic and mixed cortical cultures to investigate the contribution of astrocyte-mediated inflammatory responses during Aβ-induced neuronal loss. We report that the presence of small numbers of astrocytes exacerbate Aβ-induced neuronal death, caspase-3 activation and the production of caspase-3-cleaved tau. Furthermore, we show that astrocytes are essential for the Aβ-induced tau phosphorylation observed in primary neurons. The release of soluble inflammatory factor(s) from astrocytes accompanies these events, and inhibition of astrocyte activation with the anti-inflammatory agent, minocycline, reduces astrocytic inflammatory responses and the associated neuronal loss. Aβ-induced increases in caspase-3 activation and the production of caspase-3-truncated tau species in neurons were reduced when the astrocytic response was attenuated with minocycline. Taken together, these results show that astrocytes are important mediators of the neurotoxic events downstream of elevated Aβ in models of AD, and suggest that mechanisms underlying pro-inflammatory cytokine release might be an important target for therapy. Nature Publishing Group 2011-06 2011-06-02 /pmc/articles/PMC3168992/ /pubmed/21633390 http://dx.doi.org/10.1038/cddis.2011.50 Text en Copyright © 2011 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Garwood, C J
Pooler, A M
Atherton, J
Hanger, D P
Noble, W
Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title_full Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title_fullStr Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title_full_unstemmed Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title_short Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture
title_sort astrocytes are important mediators of aβ-induced neurotoxicity and tau phosphorylation in primary culture
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168992/
https://www.ncbi.nlm.nih.gov/pubmed/21633390
http://dx.doi.org/10.1038/cddis.2011.50
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