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PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment

83 Pages Posted: 2 Jan 2019

See all articles by Luca Kleineidam

Luca Kleineidam

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Vincent Chouraki

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases

Thomas Próchnicki

University of Bonn - Institute of Innate Immunity

Sven van der Lee

VU University Amsterdam - Department of Neurology

Laura Madrid-Márquez

Andalusian Bioinformatics Research Centre (CAEBi)

Holger Wagner-Thelen

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Ilker Karaca

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Leonie Weinhold

University of Bonn - Institute for Medical Biometry, Informatics and Epidemiology (IMBIE)

Steffen Wolfsgruber

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Anne Boland

University of Paris-Saclay

Pamela V. Martino Adami

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Piotr Lewczuk

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg; Medical University of Bialystok

Julius Popp

University of Lausanne - Department of Psychiatry

Frederic Brosseron

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Iris Jansen

VU University Amsterdam - Department of Neurology

Marc Hulsman

VU University Amsterdam - Department of Neurology

Johannes Kornhuber

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg

Oliver Peters

Charité - Universitätsmedizin Berlin - Department of Psychiatry and Psychotherapy

Claudine Berr

University of Montpellier

Reinhard Heun

University of Bonn, Faculty of Medicine, Department of Psychiatry and Psychotherapy

Lutz Frölich

Heidelberg University - Central Institute of Mental Health

Christopher Tzourio

University of Bordeaux - Bordeaux Population Health Research Center

Jean-François Dartigues

University of Bordeaux - Victor Segalen Bordeaux 2 University

Michael Hüll

University of Freiburg - Department of Psychiatry and Psychotherapy

Ana Espinosa

Universitat Internacional de Catalunya

Isabel Hernandez

Carlos III Institute of Health

Itziar de Rojas

Carlos III Institute of Health

Adela Orellana

Universitat Internacional de Catalunya

Sergi Valero

Universitat Internacional de Catalunya

Najada Stringa

VU University Amsterdam - Amsterdam Public Health Research Institute

Natasja M. van Schoor

University of Amsterdam - Amsterdam Public Health Research Institute

Martijn A. Huisman

VU University Amsterdam - Amsterdam Public Health Research Institute

Philip Scheltens

VU University Amsterdam - Department of Neurology

Eckart Rüther

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy

Jean-Francois Deleuze

University of Paris-Saclay

Jens Wiltfang

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy; German Center for Neurodegenerative Diseases (DZNE); Universidade de Aveiro - Institute for Research in Biomedicine (iBiMED)

Lluis Tarraga

Universitat Internacional de Catalunya

Matthias Schmid

German Center for Neurodegenerative Diseases (DZNE)

Martin Scherer

University Medical Center Hamburg-Eppendorf

Steffi Riedel-Heller

University of Leipzig - Institute for Social Medicine, Occupational Health and Public Health

Michael T. Heneka

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Philippe Amouyel

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases; Early Markers of Cardiovascular Remodeling in Valvulopathy and Heart Failure; University Hospital of Lille; University of Lille

Frank Jessen

German Center for Neurodegenerative Diseases (DZNE)

Merce Boada

Carlos III Institute of Health

Wolfgang Maier

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Anja Schneider

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry; German Center for Neurodegenerative Diseases (DZNE)

Antonio González-Pérez

Andalusian Bioinformatics Research Centre (CAEBi)

Wiesje M. van der Flier

University of Bonn - Institute of Innate Immunity

Michael Wagner

University of Bonn, Faculty of Medicine, Department of Psychiatry and Psychotherapy

Jean-Charles Lambert

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases

Henne Holstege

VU University Amsterdam - Department of Neurology

Mª Eugenia Sáez

Andalusian Bioinformatics Research Centre (CAEBi)

Eicke Latz

German Center for Neurodegenerative Diseases (DZNE); University of Bonn - Institute of Innate Immunity; University of Massachusetts Worcester - Department of Medicine

Agustin Ruiz

Universitat Internacional de Catalunya

Alfredo Ramirez

University of Cologne - Division of Neurogenetics and Molecular Psychiatry; University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

More...

Abstract

Background: A rare coding variant (rs72824905, p.P522R) conferring protection against the susceptibility to Alzheimer's disease (AD) was recently identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2). Here, we explore the protective nature of this variant with regard to AD pathology indicated by biomarkers, cognitive decline, and potential underlying biological mechanisms.

Methods: Association of p.P522R with CSF levels of pTau181, total Tau and Aβ1-42 was assessed in 1,282 patients with mild cognitive impairment (MCI) or AD-dementia syndrome. In addition, the association with longitudinal cognitive decline was tested in 3,010 MCI patients from memory clinic cohorts and 10,100 individuals from population-based studies using latent process linear mixed models. Finally, unsupervised co-trans-regulatory network analysis and biological experiments were conducted. 

Findings: Carriers of the p.P522R variant showed lower pTau181 levels in CSF compared to non-carriers, specifically in the presence of amyloid pathology. In MCI patients but not in population-based cohorts, the p.P522R variant was associated with slower cognitive decline with an effect size similar to that of APOE-ε4. We identified a network of coregulated proteins linking PLCG2 to APOE and TREM2. Finally, in vitro experiments confirmed that inflammasome activation upon phospholipase C stimulation might act downstream of PLCG2.

Implication: Our data link the protective effect of p.P522R in PLCG2 to reduced Tau pathology, to a slower cognitive decline in MCI patients and to underlying inflammatory processes. Therapies targeting the enzyme PLCG2 might provide a therapeutic approach for AD.

Funding Statement: EU Joint Programme Neurodegenerative Disease Research, Innovative Medicines Initiative 2, Instituto de Salud Carlos III, La Caixa, Grifols SA, German Federal Ministry of Research and Education, Sanofi Laboratories, Fondation pour la Recherche Médicale, Fondation Plan Alzheimer, Stichting Alzheimer Nederland, Stichting VUmc fonds, Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care, Netherlands Organization for Scientific Research (NWO), EMGO+ Research Institute.  

Declaration of Interests: All authors report no conflict of interest. PL received consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. JW received honoraria for consulting activities, lectures or advisory board participation from Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim. LF received honoraria for consulting activities, lectures or advisory board participation from Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe & Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Jülich, Novartis, Pharmatropix. JP received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestlé Institute of Health Sciences. ARu reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, Foundation Alzheimer. OP received research funding, consultancy fees or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda and TauRx Pharmaceuticals. MB receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, Servier. She receives fees for being part of the Advisory Board of Lilly and Schwabe. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp & Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations

Ethics Approval Statement: The individual studies were approved by the respective ethics committees.

Suggested Citation

Kleineidam, Luca and Chouraki, Vincent and Próchnicki, Thomas and van der Lee, Sven and Madrid-Márquez, Laura and Wagner-Thelen, Holger and Karaca, Ilker and Weinhold, Leonie and Wolfsgruber, Steffen and Boland, Anne and Martino Adami, Pamela V. and Lewczuk, Piotr and Popp, Julius and Brosseron, Frederic and Jansen, Iris and Hulsman, Marc and Kornhuber, Johannes and Peters, Oliver and Berr, Claudine and Heun, Reinhard and Frölich, Lutz and Tzourio, Christopher and Dartigues, Jean-François and Hüll, Michael and Espinosa, Ana and Hernandez, Isabel and de Rojas, Itziar and Orellana, Adela and Valero, Sergi and Stringa, Najada and van Schoor, Natasja M. and Huisman, Martijn A. and Scheltens, Philip and Rüther, Eckart and Deleuze, Jean-Francois and Wiltfang, Jens and Tarraga, Lluis and Schmid, Matthias and Scherer, Martin and Riedel-Heller, Steffi and Heneka, Michael T. and Amouyel, Philippe and Jessen, Frank and Boada, Merce and Maier, Wolfgang and Schneider, Anja and González-Pérez, Antonio and van der Flier, Wiesje M. and Wagner, Michael and Lambert, Jean-Charles and Holstege, Henne and Sáez, Mª Eugenia and Latz, Eicke and Ruiz, Agustin and Ramirez, Alfredo, PLCG2 Protective Variant p.P522R Modulates Tau Pathology and Disease Progression in Patients with Mild Cognitive Impairment (December 29, 2018). Available at SSRN: https://ssrn.com/abstract=3307649

Luca Kleineidam

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Kerpener Strasse 62
Cologne, 50924
Germany

Vincent Chouraki

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases ( email )

Lille
France

Thomas Próchnicki

University of Bonn - Institute of Innate Immunity

Bonn
Germany

Sven Van der Lee

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Laura Madrid-Márquez

Andalusian Bioinformatics Research Centre (CAEBi)

Seville
Spain

Holger Wagner-Thelen

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Kerpener Strasse 62
Cologne, 50924
Germany

Ilker Karaca

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Leonie Weinhold

University of Bonn - Institute for Medical Biometry, Informatics and Epidemiology (IMBIE)

Sigmund-Freud-Str. 25
Bonn, 53127
Germany

Steffen Wolfsgruber

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Anne Boland

University of Paris-Saclay

55 Avenue de Paris
Versailles, 78000
France

Pamela V. Martino Adami

University of Cologne - Division of Neurogenetics and Molecular Psychiatry

Kerpener Strasse 62
Cologne, 50924
Germany

Piotr Lewczuk

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg

Schloßplatz 4
Erlangen, Bavaria 91054
Germany

Medical University of Bialystok

Białystok
Poland

Julius Popp

University of Lausanne - Department of Psychiatry

Prilly, 1008
Switzerland

Frederic Brosseron

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Iris Jansen

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Marc Hulsman

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Johannes Kornhuber

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg

Schloßplatz 4
Erlangen, Bavaria 91054
Germany

Oliver Peters

Charité - Universitätsmedizin Berlin - Department of Psychiatry and Psychotherapy

Charitéplatz 1
Berlin, 10117
Germany

Claudine Berr

University of Montpellier

163 rue Auguste Broussonnet
France

Reinhard Heun

University of Bonn, Faculty of Medicine, Department of Psychiatry and Psychotherapy

Germany

Lutz Frölich

Heidelberg University - Central Institute of Mental Health

Mannheim, 68159
Germany

Christopher Tzourio

University of Bordeaux - Bordeaux Population Health Research Center

France

Jean-François Dartigues

University of Bordeaux - Victor Segalen Bordeaux 2 University ( email )

146 rue Leo Saignat
F-33076 Bordeax Cedex
France

Michael Hüll

University of Freiburg - Department of Psychiatry and Psychotherapy

Freiburg
Germany

Ana Espinosa

Universitat Internacional de Catalunya ( email )

Immaculada 22
Barcelona, 08017
Spain

Isabel Hernandez

Carlos III Institute of Health ( email )

Spain

Itziar De Rojas

Carlos III Institute of Health

c/ Monforte de Lemos 5
Madrid, Madrid 28029
Spain

Adela Orellana

Universitat Internacional de Catalunya

Immaculada 22
Barcelona, 08017
Spain

Sergi Valero

Universitat Internacional de Catalunya ( email )

Immaculada 22
Barcelona, 08017
Spain

Najada Stringa

VU University Amsterdam - Amsterdam Public Health Research Institute

Amsterdam
Netherlands

Natasja M. Van Schoor

University of Amsterdam - Amsterdam Public Health Research Institute

Meibergdreef 9
Amsterdam, 1105
Netherlands

Martijn A. Huisman

VU University Amsterdam - Amsterdam Public Health Research Institute

Amsterdam
Netherlands

Philip Scheltens

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Eckart Rüther

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy

Germany

Jean-Francois Deleuze

University of Paris-Saclay

55 Avenue de Paris
Versailles, 78000
France

Jens Wiltfang

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy ( email )

Germany

German Center for Neurodegenerative Diseases (DZNE) ( email )

von Siebold Strasse 3a
Goettingen, 37075
Germany

Universidade de Aveiro - Institute for Research in Biomedicine (iBiMED) ( email )

Aveiro
Portugal

Lluis Tarraga

Universitat Internacional de Catalunya

Immaculada 22
Barcelona, 08017
Spain

Matthias Schmid

German Center for Neurodegenerative Diseases (DZNE)

von Siebold Strasse 3a
Goettingen, 37075
Germany

Martin Scherer

University Medical Center Hamburg-Eppendorf

Martinistrasse 52
Hamburg, 20246
Germany

Steffi Riedel-Heller

University of Leipzig - Institute for Social Medicine, Occupational Health and Public Health

Leipzig, 04103
Germany

Michael T. Heneka

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Philippe Amouyel

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases

Lille
France

Early Markers of Cardiovascular Remodeling in Valvulopathy and Heart Failure ( email )

France

University Hospital of Lille

2 Avenue Oscar Lambret
Lille, 59000
France

University of Lille

Cité Scientifique
Villeneuve-d'Ascq, 59650
France

Frank Jessen

German Center for Neurodegenerative Diseases (DZNE)

von Siebold Strasse 3a
Goettingen, 37075
Germany

Merce Boada

Carlos III Institute of Health

Spain

Wolfgang Maier

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Anja Schneider

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry ( email )

Bonn, 53127
Germany

German Center for Neurodegenerative Diseases (DZNE) ( email )

von Siebold Strasse 3a
Goettingen, 37075
Germany

Antonio González-Pérez

Andalusian Bioinformatics Research Centre (CAEBi)

Seville
Spain

Wiesje M. Van der Flier

University of Bonn - Institute of Innate Immunity

Bonn
Germany

Michael Wagner

University of Bonn, Faculty of Medicine, Department of Psychiatry and Psychotherapy ( email )

Germany

Jean-Charles Lambert

University of Lille II - RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases

Lille
France

Henne Holstege

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Mª Eugenia Sáez

Andalusian Bioinformatics Research Centre (CAEBi)

Seville
Spain

Eicke Latz

German Center for Neurodegenerative Diseases (DZNE)

von Siebold Strasse 3a
Goettingen, 37075
Germany

University of Bonn - Institute of Innate Immunity

Bonn
Germany

University of Massachusetts Worcester - Department of Medicine

55 Lake Avenue North
Worcester, MA 01655
United States

Agustin Ruiz

Universitat Internacional de Catalunya

Immaculada 22
Barcelona, 08017
Spain

Alfredo Ramirez (Contact Author)

University of Cologne - Division of Neurogenetics and Molecular Psychiatry ( email )

Kerpener Strasse 62
Cologne, 50924
Germany

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry ( email )

Bonn, 53127
Germany

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