Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2019 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/55392 |
Resumo: | © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
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Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptorA2A receptorC1qAdenosineMicrogliaTau© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAccumulating data support the role of tau pathology in cognitive decline in ageing and Alzheimer's disease, but underlying mechanisms remain ill-defined. Interestingly, ageing and Alzheimer's disease have been associated with an abnormal upregulation of adenosine A2A receptor (A2AR), a fine tuner of synaptic plasticity. However, the link between A2AR signalling and tau pathology has remained largely unexplored. In the present study, we report for the first time a significant upregulation of A2AR in patients suffering from frontotemporal lobar degeneration with the MAPT P301L mutation. To model these alterations, we induced neuronal A2AR upregulation in a tauopathy mouse model (THY-Tau22) using a new conditional strain allowing forebrain overexpression of the receptor. We found that neuronal A2AR upregulation increases tau hyperphosphorylation, potentiating the onset of tau-induced memory deficits. This detrimental effect was linked to a singular microglial signature as revealed by RNA sequencing analysis. In particular, we found that A2AR overexpression in THY-Tau22 mice led to the hippocampal upregulation of C1q complement protein-also observed in patients with frontotemporal lobar degeneration-and correlated with the loss of glutamatergic synapses, likely underlying the observed memory deficits. These data reveal a key impact of overactive neuronal A2AR in the onset of synaptic loss in tauopathies, paving the way for new therapeutic approaches.This work was supported by grants from Hauts-de-France (PARTEN-AIRR, COGNADORA), ANR (ADORATAU to D.B.) and Programs d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease). Our laboratories are also supported by ANR (GRAND, SPREADTAU to LB, ADORASTrAU to D.B.), Fondation pour la Recherche Médicale, France Alzheimer/Fondation de France, FHU VasCog research network (Lille, France), Fondation Vaincre Alzheimer, Fondation Plan Alzheimer as well as Inserm, CNRS, Université Lille, Lille Métropole Communauté Urbaine, DN2M. K.C. holds a doctoral grant from Lille University. V.G-M. was supported by Fondation pour la Recherche Médicale (SPF20160936000). C.M. is supported by Région Hauts-de-France. X.M. and S.L. are funded by ANR (ADONIS), Fondation pour la Recherche Médicale et Fondation pour la Recherche sur le Cerveau. A.L.B. is supported by CNRS, Unistra, ANR-16-CE92-0031 (EPIFUS), Alsace Alzheimer 67, France Alzheimer (AAP SM 2017 #1664). L.V.L. and J.E.C. are funded by Fundaçao para a Ciência e Tecnologia (PTDC/4778/2014).Oxford University PressRepositório da Universidade de LisboaCarvalho, KevinFaivre, EmiliePietrowski, Marie J.Marques, XavierGomez-Murcia, VictoriaDeleau, AudeHuin, VincentHansen, Jan NKozlov, StanislavDanis, ClémentTemido Ferreira, MarianaCoelho, Joana EMériaux, CélineEddarkaoui, SabihaGras, Stéphanie LeDumoulin, MélanieCellai, LucreziaLandrieu, IsabelleChern, YijuangHamdane, MalikaBuée, LucBoutillier, Anne-LaurenceLevi, SabineHalle, AnnettLopes, Luisa V.Blum, David2022-12-14T13:48:51Z20192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/55392engBrain. 2019 Nov 1;142(11):3636-36540006-895010.1093/brain/awz2881460-2156info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:02:19Zoai:repositorio.ul.pt:10451/55392Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:06:02.830215Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| title |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| spellingShingle |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor Carvalho, Kevin A2A receptor C1q Adenosine Microglia Tau |
| title_short |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| title_full |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| title_fullStr |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| title_full_unstemmed |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| title_sort |
Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor |
| author |
Carvalho, Kevin |
| author_facet |
Carvalho, Kevin Faivre, Emilie Pietrowski, Marie J. Marques, Xavier Gomez-Murcia, Victoria Deleau, Aude Huin, Vincent Hansen, Jan N Kozlov, Stanislav Danis, Clément Temido Ferreira, Mariana Coelho, Joana E Mériaux, Céline Eddarkaoui, Sabiha Gras, Stéphanie Le Dumoulin, Mélanie Cellai, Lucrezia Landrieu, Isabelle Chern, Yijuang Hamdane, Malika Buée, Luc Boutillier, Anne-Laurence Levi, Sabine Halle, Annett Lopes, Luisa V. Blum, David |
| author_role |
author |
| author2 |
Faivre, Emilie Pietrowski, Marie J. Marques, Xavier Gomez-Murcia, Victoria Deleau, Aude Huin, Vincent Hansen, Jan N Kozlov, Stanislav Danis, Clément Temido Ferreira, Mariana Coelho, Joana E Mériaux, Céline Eddarkaoui, Sabiha Gras, Stéphanie Le Dumoulin, Mélanie Cellai, Lucrezia Landrieu, Isabelle Chern, Yijuang Hamdane, Malika Buée, Luc Boutillier, Anne-Laurence Levi, Sabine Halle, Annett Lopes, Luisa V. Blum, David |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Carvalho, Kevin Faivre, Emilie Pietrowski, Marie J. Marques, Xavier Gomez-Murcia, Victoria Deleau, Aude Huin, Vincent Hansen, Jan N Kozlov, Stanislav Danis, Clément Temido Ferreira, Mariana Coelho, Joana E Mériaux, Céline Eddarkaoui, Sabiha Gras, Stéphanie Le Dumoulin, Mélanie Cellai, Lucrezia Landrieu, Isabelle Chern, Yijuang Hamdane, Malika Buée, Luc Boutillier, Anne-Laurence Levi, Sabine Halle, Annett Lopes, Luisa V. Blum, David |
| dc.subject.por.fl_str_mv |
A2A receptor C1q Adenosine Microglia Tau |
| topic |
A2A receptor C1q Adenosine Microglia Tau |
| description |
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019 2019-01-01T00:00:00Z 2022-12-14T13:48:51Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/55392 |
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http://hdl.handle.net/10451/55392 |
| dc.language.iso.fl_str_mv |
eng |
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eng |
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Brain. 2019 Nov 1;142(11):3636-3654 0006-8950 10.1093/brain/awz288 1460-2156 |
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openAccess |
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Oxford University Press |
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Oxford University Press |
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