PLCG2 protective variant p.P522R modulates ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Title :
PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
Author(s) :
Kleineidam, Luca [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universität zu Köln = University of Cologne
University Hospital Bonn
Chouraki, Vincent [Auteur]
Service d'Epidémiologie et de Santé Publique [Lille]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Próchnicki, Tomasz [Auteur]
University Hospital Bonn
van Der Lee, Sven [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Madrid‑márquez, Laura [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Wagner-Thelen, Holger [Auteur]
Universität zu Köln = University of Cologne
University Hospital Bonn
Karaca, Ilker [Auteur]
University Hospital Bonn
Weinhold, Leonie [Auteur]
University Hospital Bonn
Wolfsgruber, Steffen [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Boland, Anne [Auteur]
Institut de Biologie François JACOB [JACOB]
Centre National de Recherche en Génomique Humaine [CNRGH]
Martino Adami, Pamela [Auteur]
Universität zu Köln = University of Cologne
Lewczuk, Piotr [Auteur]
University of Bialystok
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Universitätsklinikum Erlangen [Erlangen]
Popp, Julius [Auteur]
University hospital of Zurich [Zurich]
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne] [CHUV]
Brosseron, Frederic [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Jansen, Iris [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Hulsman, Marc [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Kornhuber, Johannes [Auteur]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Universitätsklinikum Erlangen [Erlangen]
Peters, Oliver [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Charité - UniversitätsMedizin = Berlin University Medicine
Berr, Claudine [Auteur]
Neuropsychiatrie : recherche épidémiologique et clinique [PSNREC]
Heun, Reinhard [Auteur]
University Hospital Bonn
Frölich, Lutz [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Tzourio, Christophe [Auteur]
Bordeaux population health [BPH]
Dartigues, Jean-François [Auteur]
Bordeaux population health [BPH]
Hüll, Michael [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Espinosa, Ana [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Hernández, Isabel [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
De Rojas, Itziar [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Orellana, Adelina [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Valero, Sergi [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Stringa, Najada [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
van Schoor, Natasja [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Huisman, Martijn [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Scheltens, Philip [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
For The Alzheimer'S Disease Neuroimaging Initiative, (adni) [Auteur]
Rüther, Eckart [Auteur]
University Medical Center Göttingen [UMG]
Deleuze, Jean-François [Auteur]
Institut de Biologie François JACOB [JACOB]
Centre National de Recherche en Génomique Humaine [CNRGH]
Wiltfang, Jens [Auteur]
Universidade de Aveiro
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Medical Center Göttingen [UMG]
Tarraga, Lluis [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Schmid, Matthias [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Scherer, Martin [Auteur]
Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] [UKE]
Riedel-Heller, Steffi [Auteur]
Leipzig University / Universität Leipzig
Heneka, Michael [Auteur]
University of Massachusetts Medical School [Worcester] [UMASS]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Amouyel, Philippe [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Jessen, Frank [Auteur]
Universität zu Köln = University of Cologne
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Boada, Merce [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Maier, Wolfgang [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Schneider, Anja [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
González‑pérez, Antonio [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
van Der Flier, Wiesje [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Wagner, Michael [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Lambert, Jean-Charles [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Holstege, Henne [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Saez, Mª Eugenia [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Latz, Eicke [Auteur]
Norwegian University of Science and Technology [Trondheim] [NTNU]
University of Massachusetts Medical School [Worcester] [UMASS]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Ruiz, Agustin [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Ramirez, Alfredo [Auteur correspondant]
Universität zu Köln = University of Cologne
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universität zu Köln = University of Cologne
University Hospital Bonn
Chouraki, Vincent [Auteur]

Service d'Epidémiologie et de Santé Publique [Lille]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Próchnicki, Tomasz [Auteur]
University Hospital Bonn
van Der Lee, Sven [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Madrid‑márquez, Laura [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Wagner-Thelen, Holger [Auteur]
Universität zu Köln = University of Cologne
University Hospital Bonn
Karaca, Ilker [Auteur]
University Hospital Bonn
Weinhold, Leonie [Auteur]
University Hospital Bonn
Wolfsgruber, Steffen [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Boland, Anne [Auteur]
Institut de Biologie François JACOB [JACOB]
Centre National de Recherche en Génomique Humaine [CNRGH]
Martino Adami, Pamela [Auteur]
Universität zu Köln = University of Cologne
Lewczuk, Piotr [Auteur]
University of Bialystok
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Universitätsklinikum Erlangen [Erlangen]
Popp, Julius [Auteur]
University hospital of Zurich [Zurich]
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne] [CHUV]
Brosseron, Frederic [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Jansen, Iris [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Hulsman, Marc [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Kornhuber, Johannes [Auteur]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Universitätsklinikum Erlangen [Erlangen]
Peters, Oliver [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Charité - UniversitätsMedizin = Berlin University Medicine
Berr, Claudine [Auteur]
Neuropsychiatrie : recherche épidémiologique et clinique [PSNREC]
Heun, Reinhard [Auteur]
University Hospital Bonn
Frölich, Lutz [Auteur]
Universität Heidelberg [Heidelberg] = Heidelberg University
Tzourio, Christophe [Auteur]
Bordeaux population health [BPH]
Dartigues, Jean-François [Auteur]
Bordeaux population health [BPH]
Hüll, Michael [Auteur]
Albert-Ludwigs-Universität Freiburg = University of Freiburg
Espinosa, Ana [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Hernández, Isabel [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
De Rojas, Itziar [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Orellana, Adelina [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Valero, Sergi [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Stringa, Najada [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
van Schoor, Natasja [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Huisman, Martijn [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Scheltens, Philip [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
For The Alzheimer'S Disease Neuroimaging Initiative, (adni) [Auteur]
Rüther, Eckart [Auteur]
University Medical Center Göttingen [UMG]
Deleuze, Jean-François [Auteur]
Institut de Biologie François JACOB [JACOB]
Centre National de Recherche en Génomique Humaine [CNRGH]
Wiltfang, Jens [Auteur]
Universidade de Aveiro
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Medical Center Göttingen [UMG]
Tarraga, Lluis [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Schmid, Matthias [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Scherer, Martin [Auteur]
Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] [UKE]
Riedel-Heller, Steffi [Auteur]
Leipzig University / Universität Leipzig
Heneka, Michael [Auteur]
University of Massachusetts Medical School [Worcester] [UMASS]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Amouyel, Philippe [Auteur]

Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Jessen, Frank [Auteur]
Universität zu Köln = University of Cologne
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Boada, Merce [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Maier, Wolfgang [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Schneider, Anja [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
González‑pérez, Antonio [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
van Der Flier, Wiesje [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Wagner, Michael [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
Lambert, Jean-Charles [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Holstege, Henne [Auteur]
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Amsterdam University Medical Centers [Amsterdam UMC]
Saez, Mª Eugenia [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Latz, Eicke [Auteur]
Norwegian University of Science and Technology [Trondheim] [NTNU]
University of Massachusetts Medical School [Worcester] [UMASS]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Ruiz, Agustin [Auteur]
Instituto de Salud Carlos III [Madrid] [ISCIII]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Ramirez, Alfredo [Auteur correspondant]
Universität zu Köln = University of Cologne
University Hospital Bonn
Journal title :
Acta Neuropathologica
Pages :
1025-1044
Publisher :
Springer Verlag
Publication date :
2020-03-12
ISSN :
0001-6322
English keyword(s) :
Alzheimer’s disease
PLCG2
Phospholipase C gamma 2
Cognitive decline
Mild cognitive impairment
PLCG2
Phospholipase C gamma 2
Cognitive decline
Mild cognitive impairment
HAL domain(s) :
Sciences du Vivant [q-bio]/Génétique/Génétique humaine
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC]
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC]
English abstract : [en]
A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore ...
Show more >A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.Show less >
Show more >A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
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