PLCG2 protective variant p.P522R modulates ...
Type de document :
Compte-rendu et recension critique d'ouvrage
PMID :
Titre :
PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
Auteur(s) :
Kleineidam, Luca [Auteur]
University Hospital Bonn
Universität zu Köln = University of Cologne
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Chouraki, Vincent [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Service d'Epidémiologie et de Santé Publique [Lille]
Próchnicki, Tomasz [Auteur]
University Hospital Bonn
van der Lee, Sven [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Madrid‑márquez, Laura [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Wagner-Thelen, Holger [Auteur]
University Hospital Bonn
Universität zu Köln = University of Cologne
Karaca, Ilker [Auteur]
University Hospital Bonn
Weinhold, Leonie [Auteur]
University Hospital Bonn
Wolfsgruber, Steffen [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Boland, Anne [Auteur]
Centre National de Recherche en Génomique Humaine [CNRGH]
Institut de Biologie François JACOB [JACOB]
Martino Adami, Pamela [Auteur]
Universität zu Köln = University of Cologne
Lewczuk, Piotr [Auteur]
Universitätsklinikum Erlangen [Erlangen]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
University of Bialystok
Popp, Julius [Auteur]
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne] [CHUV]
University hospital of Zurich [Zurich]
Brosseron, Frederic [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Jansen, Iris [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Hulsman, Marc [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Kornhuber, Johannes [Auteur]
Universitätsklinikum Erlangen [Erlangen]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Peters, Oliver [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
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
Espinosa, Ana [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Hernández, Isabel [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
De Rojas, Itziar [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Orellana, Adelina [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Valero, Sergi [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Stringa, Najada [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
van Schoor, Natasja [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Huisman, Martijn [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Scheltens, Philip [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
For The Alzheimer'S Disease Neuroimaging Initiative, (adni) [Auteur]
Rüther, Eckart [Auteur]
University Medical Center Göttingen [UMG]
Deleuze, Jean-François [Auteur]
Centre National de Recherche en Génomique Humaine [CNRGH]
Institut de Biologie François JACOB [JACOB]
Wiltfang, Jens [Auteur]
University Medical Center Göttingen [UMG]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universidade de Aveiro
Tarraga, Lluis [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Schmid, Matthias [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
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 Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University of Massachusetts Medical School [Worcester] [UMASS]
Amouyel, Philippe [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Jessen, Frank [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universität zu Köln = University of Cologne
Boada, Merce [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Maier, Wolfgang [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Schneider, Anja [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
González‑pérez, Antonio [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
van der Flier, Wiesje [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Wagner, Michael [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Lambert, Jean-Charles [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Holstege, Henne [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Saez, Mª Eugenia [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Latz, Eicke [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
University of Massachusetts Medical School [Worcester] [UMASS]
Norwegian University of Science and Technology [Trondheim] [NTNU]
Ruiz, Agustin [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Ramirez, Alfredo [Auteur correspondant]
University Hospital Bonn
Universität zu Köln = University of Cologne
University Hospital Bonn
Universität zu Köln = University of Cologne
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Chouraki, Vincent [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Service d'Epidémiologie et de Santé Publique [Lille]
Próchnicki, Tomasz [Auteur]
University Hospital Bonn
van der Lee, Sven [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Madrid‑márquez, Laura [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Wagner-Thelen, Holger [Auteur]
University Hospital Bonn
Universität zu Köln = University of Cologne
Karaca, Ilker [Auteur]
University Hospital Bonn
Weinhold, Leonie [Auteur]
University Hospital Bonn
Wolfsgruber, Steffen [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Boland, Anne [Auteur]
Centre National de Recherche en Génomique Humaine [CNRGH]
Institut de Biologie François JACOB [JACOB]
Martino Adami, Pamela [Auteur]
Universität zu Köln = University of Cologne
Lewczuk, Piotr [Auteur]
Universitätsklinikum Erlangen [Erlangen]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
University of Bialystok
Popp, Julius [Auteur]
Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne] [CHUV]
University hospital of Zurich [Zurich]
Brosseron, Frederic [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Jansen, Iris [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Hulsman, Marc [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Kornhuber, Johannes [Auteur]
Universitätsklinikum Erlangen [Erlangen]
Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg [FAU]
Peters, Oliver [Auteur]
Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
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
Espinosa, Ana [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Hernández, Isabel [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
De Rojas, Itziar [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Orellana, Adelina [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Valero, Sergi [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Stringa, Najada [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
van Schoor, Natasja [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Huisman, Martijn [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Scheltens, Philip [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
For The Alzheimer'S Disease Neuroimaging Initiative, (adni) [Auteur]
Rüther, Eckart [Auteur]
University Medical Center Göttingen [UMG]
Deleuze, Jean-François [Auteur]
Centre National de Recherche en Génomique Humaine [CNRGH]
Institut de Biologie François JACOB [JACOB]
Wiltfang, Jens [Auteur]
University Medical Center Göttingen [UMG]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universidade de Aveiro
Tarraga, Lluis [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Schmid, Matthias [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
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 Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University of Massachusetts Medical School [Worcester] [UMASS]
Amouyel, Philippe [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Jessen, Frank [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Universität zu Köln = University of Cologne
Boada, Merce [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Maier, Wolfgang [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Schneider, Anja [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
González‑pérez, Antonio [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
van der Flier, Wiesje [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Wagner, Michael [Auteur]
University Hospital Bonn
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
Lambert, Jean-Charles [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Holstege, Henne [Auteur]
Amsterdam UMC - Amsterdam University Medical Center
Vrije Universiteit Amsterdam [Amsterdam] [VU]
Saez, Mª Eugenia [Auteur]
Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla] [CAEBi]
Latz, Eicke [Auteur]
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen [DZNE]
University Hospital Bonn
University of Massachusetts Medical School [Worcester] [UMASS]
Norwegian University of Science and Technology [Trondheim] [NTNU]
Ruiz, Agustin [Auteur]
Universitat Internacional de Catalunya [Barcelona] [UIC]
Instituto de Salud Carlos III [Madrid] [ISC]
Ramirez, Alfredo [Auteur correspondant]
University Hospital Bonn
Universität zu Köln = University of Cologne
Titre de la revue :
ACTA NEUROPATHOLOGICA
Pagination :
1025-1044
Éditeur :
Springer Verlag
Date de publication :
2020-03-12
ISSN :
0001-6322
Mot(s)-clé(s) en anglais :
Alzheimer’s disease
PLCG2
Phospholipase C gamma 2
Cognitive decline
Mild cognitive impairment
PLCG2
Phospholipase C gamma 2
Cognitive decline
Mild cognitive impairment
Discipline(s) HAL :
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]
Résumé en anglais : [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 ...
Lire la suite >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.Lire moins >
Lire la suite >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.Lire moins >
Langue :
Anglais
Vulgarisation :
Non
Projet ANR :
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