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Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2

Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity a...

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Autores principales: Staurenghi, Erica, Cerrato, Valentina, Gamba, Paola, Testa, Gabriella, Giannelli, Serena, Leoni, Valerio, Caccia, Claudio, Buffo, Annalisa, Noble, Wendy, Perez-Nievas, Beatriz Gomez, Leonarduzzi, Gabriella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772793/
https://www.ncbi.nlm.nih.gov/pubmed/33360775
http://dx.doi.org/10.1016/j.redox.2020.101837
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author Staurenghi, Erica
Cerrato, Valentina
Gamba, Paola
Testa, Gabriella
Giannelli, Serena
Leoni, Valerio
Caccia, Claudio
Buffo, Annalisa
Noble, Wendy
Perez-Nievas, Beatriz Gomez
Leonarduzzi, Gabriella
author_facet Staurenghi, Erica
Cerrato, Valentina
Gamba, Paola
Testa, Gabriella
Giannelli, Serena
Leoni, Valerio
Caccia, Claudio
Buffo, Annalisa
Noble, Wendy
Perez-Nievas, Beatriz Gomez
Leonarduzzi, Gabriella
author_sort Staurenghi, Erica
collection PubMed
description Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes.
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spelling pubmed-77727932020-12-31 Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2 Staurenghi, Erica Cerrato, Valentina Gamba, Paola Testa, Gabriella Giannelli, Serena Leoni, Valerio Caccia, Claudio Buffo, Annalisa Noble, Wendy Perez-Nievas, Beatriz Gomez Leonarduzzi, Gabriella Redox Biol Research Paper Among Alzheimer's disease (AD) brain hallmarks, the presence of reactive astrocytes was demonstrated to correlate with neuronal loss and cognitive deficits. Evidence indeed supports the role of reactive astrocytes as mediators of changes in neurons, including synapses. However, the complexity and the outcomes of astrocyte reactivity are far from being completely elucidated. Another key role in AD pathogenesis is played by alterations in brain cholesterol metabolism. Oxysterols (cholesterol oxidation products) are crucial for brain cholesterol homeostasis, and we previously demonstrated that changes in the brain levels of various oxysterols correlate with AD progression. Moreover, oxysterols have been shown to contribute to various pathological mechanisms involved in AD pathogenesis. In order to deepen the role of oxysterols in AD, we investigated whether they could contribute to astrocyte reactivity, and consequently impact on neuronal health. Results showed that oxysterols present in mild or severe AD brains induce a clear morphological change in mouse primary astrocytes, accompanied by the upregulation of some reactive astrocyte markers, including lipocalin-2 (Lcn2). Moreover, astrocyte conditioned media analysis revealed a significant increase in the release of Lcn2, cytokines, and chemokines in response to oxysterols. A significant reduction of postsynaptic density protein 95 (PSD95) and a concurrent increase in cleaved caspase-3 protein levels have been demonstrated in neurons co-cultured with oxysterol-treated astrocytes, pointing out that mediators released by astrocytes have an impact on neurons. Among these mediators, Lcn2 has been demonstrated to play a major role on synapses, affecting neurite morphology and decreasing dendritic spine density. These data demonstrated that oxysterols present in the AD brain promote astrocyte reactivity, determining the release of several mediators that affect neuronal health and synapses. Lcn2 has been shown to exert a key role in mediating the synaptotoxic effect of oxysterol-treated astrocytes. Elsevier 2020-12-17 /pmc/articles/PMC7772793/ /pubmed/33360775 http://dx.doi.org/10.1016/j.redox.2020.101837 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Staurenghi, Erica
Cerrato, Valentina
Gamba, Paola
Testa, Gabriella
Giannelli, Serena
Leoni, Valerio
Caccia, Claudio
Buffo, Annalisa
Noble, Wendy
Perez-Nievas, Beatriz Gomez
Leonarduzzi, Gabriella
Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title_full Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title_fullStr Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title_full_unstemmed Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title_short Oxysterols present in Alzheimer's disease brain induce synaptotoxicity by activating astrocytes: A major role for lipocalin-2
title_sort oxysterols present in alzheimer's disease brain induce synaptotoxicity by activating astrocytes: a major role for lipocalin-2
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772793/
https://www.ncbi.nlm.nih.gov/pubmed/33360775
http://dx.doi.org/10.1016/j.redox.2020.101837
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