Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.

The role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models....

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Autores: Sanchez-Mejias, Elisabeth, Navarro, Victoria, Jimenez, Sebastian, Sanchez-Mico, Maria, Sanchez-Varo, Raquel, Nuñez-Diaz, Cristina, Trujillo-Estrada, Laura, Davila, Jose Carlos, Vizuete, Marisa, Gutierrez, Antonia, Vitorica, Javier
Formato: artículo
Fecha de publicación:2016
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/17165
Acesso em linha:http://hdl.handle.net/20.500.12105/17165
Access Level:acceso abierto
Palavra-chave:Alzheimer
Hippocampus
Human brain
Microglia
Pathology
Adult
Aged
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spelling Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.Sanchez-Mejias, ElisabethNavarro, VictoriaJimenez, SebastianSanchez-Mico, MariaSanchez-Varo, RaquelNuñez-Diaz, CristinaTrujillo-Estrada, LauraDavila, Jose CarlosVizuete, MarisaGutierrez, AntoniaVitorica, JavierAlzheimerHippocampusHuman brainMicrogliaPathologyAdultAgedThe role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.20242024-01-1620162016-10-1420162016-10-14research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/17165reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/171652026-06-12T12:43:37Z
dc.title.none.fl_str_mv Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
title Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
spellingShingle Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
Sanchez-Mejias, Elisabeth
Alzheimer
Hippocampus
Human brain
Microglia
Pathology
Adult
Aged
title_short Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
title_full Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
title_fullStr Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
title_full_unstemmed Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
title_sort Soluble phospho-tau from Alzheimer's disease hippocampus drives microglial degeneration.
dc.creator.none.fl_str_mv Sanchez-Mejias, Elisabeth
Navarro, Victoria
Jimenez, Sebastian
Sanchez-Mico, Maria
Sanchez-Varo, Raquel
Nuñez-Diaz, Cristina
Trujillo-Estrada, Laura
Davila, Jose Carlos
Vizuete, Marisa
Gutierrez, Antonia
Vitorica, Javier
author Sanchez-Mejias, Elisabeth
author_facet Sanchez-Mejias, Elisabeth
Navarro, Victoria
Jimenez, Sebastian
Sanchez-Mico, Maria
Sanchez-Varo, Raquel
Nuñez-Diaz, Cristina
Trujillo-Estrada, Laura
Davila, Jose Carlos
Vizuete, Marisa
Gutierrez, Antonia
Vitorica, Javier
author_role author
author2 Navarro, Victoria
Jimenez, Sebastian
Sanchez-Mico, Maria
Sanchez-Varo, Raquel
Nuñez-Diaz, Cristina
Trujillo-Estrada, Laura
Davila, Jose Carlos
Vizuete, Marisa
Gutierrez, Antonia
Vitorica, Javier
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Alzheimer
Hippocampus
Human brain
Microglia
Pathology
Adult
Aged
topic Alzheimer
Hippocampus
Human brain
Microglia
Pathology
Adult
Aged
description The role of microglial cells in the development and progression of Alzheimer's disease (AD) has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile (dentate gyrus > CA3 > CA1 > parahippocampal gyrus), including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance ("microglial domain"). Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions (extracellular/cytosolic) from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and/or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-10-14
2016
2016-10-14
2024
2024-01-16
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/17165
url http://hdl.handle.net/20.500.12105/17165
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408865300250624
score 15.812429

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