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@ARTICLE{Reifschneider:163471,
      author       = {Reifschneider, Anika and Robinson, Sophie and van
                      Lengerich, Bettina and Gnoerich, Johannes and Logan, Todd
                      and Heindl, Steffanie and Vogt, Miriam A and Weidinger, Endy
                      and Riedl, Lina and Wind, Karin and Zatcepin, Artem and
                      Pesämaa, Ida and Haberl, Sophie and Nuscher, Brigitte and
                      Kleinberger, Gernot and Klimmt, Julien and Götzl, Julia K
                      and Liesz, Arthur and Bürger, Katharina and Brendel,
                      Matthias and Levin, Johannes and Diehl-Schmid, Janine and
                      Suh, Jung and Di Paolo, Gilbert and Lewcock, Joseph W and
                      Monroe, Kathryn M and Paquet, Dominik and Capell, Anja and
                      Haass, Christian},
      title        = {{L}oss of {TREM}2 rescues hyperactivation of microglia, but
                      not lysosomal deficits and neurotoxicity in models of
                      progranulin deficiency.},
      journal      = {The EMBO journal},
      volume       = {41},
      number       = {4},
      issn         = {1460-2075},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2022-00231},
      pages        = {e109108},
      year         = {2022},
      note         = {(CC BY-NC-ND)},
      abstract     = {Haploinsufficiency of the progranulin (PGRN)-encoding gene
                      (GRN) causes frontotemporal lobar degeneration (GRN-FTLD)
                      and results in microglial hyperactivation, TREM2 activation,
                      lysosomal dysfunction, and TDP-43 deposition. To understand
                      the contribution of microglial hyperactivation to pathology,
                      we used genetic and pharmacological approaches to suppress
                      TREM2-dependent transition of microglia from a homeostatic
                      to a disease-associated state. Trem2 deficiency in Grn KO
                      mice reduced microglia hyperactivation. To explore
                      antibody-mediated pharmacological modulation of
                      TREM2-dependent microglial states, we identified
                      antagonistic TREM2 antibodies. Treatment of macrophages from
                      GRN-FTLD patients with these antibodies led to reduced TREM2
                      signaling due to its enhanced shedding. Furthermore, TREM2
                      antibody-treated PGRN-deficient microglia derived from
                      human-induced pluripotent stem cells showed reduced
                      microglial hyperactivation, TREM2 signaling, and phagocytic
                      activity, but lysosomal dysfunction was not rescued.
                      Similarly, lysosomal dysfunction, lipid dysregulation, and
                      glucose hypometabolism of Grn KO mice were not rescued by
                      TREM2 ablation. Synaptic loss and neurofilament light-chain
                      (NfL) levels, a biomarker for neurodegeneration, were
                      further elevated in the Grn/Trem2 KO cerebrospinal fluid
                      (CSF). These findings suggest that TREM2-dependent microglia
                      hyperactivation in models of GRN deficiency does not promote
                      neurotoxicity, but rather neuroprotection.},
      keywords     = {Animals / Antibodies: immunology / Antibodies: pharmacology
                      / Brain: diagnostic imaging / Brain: physiopathology /
                      Disease Models, Animal / Female / Frontotemporal Lobar
                      Degeneration: metabolism / Frontotemporal Lobar
                      Degeneration: pathology / Humans / Lysosomes: metabolism /
                      Lysosomes: pathology / Male / Membrane Glycoproteins:
                      genetics / Membrane Glycoproteins: immunology / Membrane
                      Glycoproteins: metabolism / Mice, Inbred C57BL / Mice,
                      Knockout / Microglia: drug effects / Microglia: physiology /
                      Monocytes: drug effects / Monocytes: metabolism /
                      Progranulins: deficiency / Receptors, Immunologic: genetics
                      / Receptors, Immunologic: immunology / Receptors,
                      Immunologic: metabolism / Syk Kinase: metabolism /
                      frontotemporal lobar degeneration (Other) / lysosomes
                      (Other) / microglia (Other) / neurodegeneration (Other) /
                      progranulin (Other) / Antibodies (NLM Chemicals) / Grn
                      protein, mouse (NLM Chemicals) / Membrane Glycoproteins (NLM
                      Chemicals) / Progranulins (NLM Chemicals) / Receptors,
                      Immunologic (NLM Chemicals) / TREM2 protein, human (NLM
                      Chemicals) / Trem2 protein, mouse (NLM Chemicals) / SYK
                      protein, human (NLM Chemicals) / Syk Kinase (NLM Chemicals)},
      cin          = {AG Haass / AG Dichgans},
      ddc          = {570},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)5000022},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35019161},
      pmc          = {pmc:PMC8844989},
      doi          = {10.15252/embj.2021109108},
      url          = {https://pub.dzne.de/record/163471},
}