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The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes beneficial microglial functions

Mari Takalo, Rebekka Wittrahm, Benedikt Wefers, Samira Parhizkar, Kimmo Jokivarsi, Teemu Kuulasmaa, Petra Mäkinen, Henna Martiskainen, Wolfgang Wurst, Xianyuan Xiang, Mikael Marttinen, Pekka Poutiainen, Annakaisa Haapasalo, Mikko Hiltunen, Christian Haass
doi: https://doi.org/10.1101/2020.04.08.031567
Mari Takalo
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Rebekka Wittrahm
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Benedikt Wefers
2Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), München, Munich, Germany
3Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany
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Samira Parhizkar
4Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
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Kimmo Jokivarsi
5A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
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Teemu Kuulasmaa
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Petra Mäkinen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Henna Martiskainen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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Wolfgang Wurst
2Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), München, Munich, Germany
3Institute of Developmental Genetics, Helmholtz Zentrum München, Munich, Germany
8Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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Xianyuan Xiang
4Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
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Mikael Marttinen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
6Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
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Pekka Poutiainen
7Center of Diagnostic Imaging, Department of Cyclotron and Radiopharmacy, Kuopio University Hospital, Kuopio, Finland
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Annakaisa Haapasalo
5A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
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Mikko Hiltunen
1Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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  • For correspondence: Christian.Haass@mail03.med.uni-muenchen.de mikko.hiltunen@uef.fi
Christian Haass
2Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), München, Munich, Germany
4Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
8Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
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  • For correspondence: Christian.Haass@mail03.med.uni-muenchen.de mikko.hiltunen@uef.fi
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Abstract

Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) selectively expressed in microglia and macrophages was recently identified and shown to reduce the risk for AD.

Methods To assess the role of this variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing.

Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival, enhanced phagocytic activity, and increased acute inflammatory response of the KI cells. Enhanced phagocytosis was also observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Furthermore, the brain mRNA signature together with microglia-specific PET imaging indicated microglia activation in Plcγ2-P522R KI mice.

Conclusion Thus, we have delineated cellular mechanisms of the protective Plcγ2-P522R variant, which provide further support for the emerging idea that activated microglia exert protective functions in AD.

  • List of abbreviations

    Plcγ2
    phospholipase C gamma 2
    Pip2
    phosphatidylinositol 4,5-bisphosphate
    Ip3
    1,4,5-trisphosphate
    Dag
    diacylglycerol
    Trem2
    Triggering receptor expressed on myeloid cells 2
    Nfκb
    nuclear factor kappa-light-chain-enhancer of activated B cells
    Mapk/Erk
    mitogen-activated protein kinase
    Akt
    protein kinase B
    KI
    knock-in
    WT
    wild type
    BMDM
    bone marrow-derived macrophage
    Ip1
    inositol monophosphate
    LPS
    lipopolysaccharide
    IFNγ
    interferon gamma
    TNFα
    tumor necrosis factor alpha
    IL-6
    interleukin-6
    IL-1β
    interleukin 1 beta
    NO
    nitric oxide
    DAM
    disease associated microglia
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    Posted April 09, 2020.
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    The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes beneficial microglial functions
    Mari Takalo, Rebekka Wittrahm, Benedikt Wefers, Samira Parhizkar, Kimmo Jokivarsi, Teemu Kuulasmaa, Petra Mäkinen, Henna Martiskainen, Wolfgang Wurst, Xianyuan Xiang, Mikael Marttinen, Pekka Poutiainen, Annakaisa Haapasalo, Mikko Hiltunen, Christian Haass
    bioRxiv 2020.04.08.031567; doi: https://doi.org/10.1101/2020.04.08.031567
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    The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes beneficial microglial functions
    Mari Takalo, Rebekka Wittrahm, Benedikt Wefers, Samira Parhizkar, Kimmo Jokivarsi, Teemu Kuulasmaa, Petra Mäkinen, Henna Martiskainen, Wolfgang Wurst, Xianyuan Xiang, Mikael Marttinen, Pekka Poutiainen, Annakaisa Haapasalo, Mikko Hiltunen, Christian Haass
    bioRxiv 2020.04.08.031567; doi: https://doi.org/10.1101/2020.04.08.031567

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