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@ARTICLE{Schlepckow:151484,
      author       = {Schlepckow, Kai and Monroe, Kathryn M and Kleinberger,
                      Gernot and Cantuti-Castelvetri, Ludovico and Parhizkar,
                      Samira and Xia, Dan and Willem, Michael and Werner, Georg
                      and Pettkus, Nadine and Brunner, Bettina and Sülzen, Alice
                      and Nuscher, Brigitte and Hampel, Heike and Xiang, Xianyuan
                      and Feederle, Regina and Tahirovic, Sabina and Park, Joshua
                      I and Prorok, Rachel and Mahon, Cathal and Liang, Chun‐Chi
                      and Shi, Ju and Kim, Do Jin and Sabelström, Hanna and
                      Huang, Fen and Di Paolo, Gilbert and Simons, Mikael and
                      Lewcock, Joseph W and Haass, Christian},
      title        = {{E}nhancing protective microglial activities with a dual
                      function {TREM} 2 antibody to the stalk region},
      journal      = {EMBO molecular medicine},
      volume       = {12},
      number       = {4},
      issn         = {1757-4676},
      address      = {Heidelberg},
      publisher    = {EMBO Press},
      reportid     = {DZNE-2020-01072},
      pages        = {e11227},
      year         = {2020},
      abstract     = {Triggering receptor expressed on myeloid cells 2 (TREM2) is
                      essential for the transition of homeostatic microglia to a
                      disease‐associated microglial state. To enhance TREM2
                      activity, we sought to selectively increase the
                      full‐length protein on the cell surface via reducing its
                      proteolytic shedding by A Disintegrin And Metalloproteinase
                      (i.e., α‐secretase) 10/17. We screened a panel of
                      monoclonal antibodies against TREM2, with the aim to
                      selectively compete for α‐secretase‐mediated shedding.
                      Monoclonal antibody 4D9, which has a stalk region epitope
                      close to the cleavage site, demonstrated dual mechanisms of
                      action by stabilizing TREM2 on the cell surface and reducing
                      its shedding, and concomitantly activating phospho‐SYK
                      signaling. 4D9 stimulated survival of macrophages and
                      increased microglial uptake of myelin debris and amyloid
                      β‐peptide in vitro. In vivo target engagement was
                      demonstrated in cerebrospinal fluid, where nearly all
                      soluble TREM2 was 4D9‐bound. Moreover, in a mouse model
                      for Alzheimer's disease‐related pathology, 4D9 reduced
                      amyloidogenesis, enhanced microglial TREM2 expression, and
                      reduced a homeostatic marker, suggesting a protective
                      function by driving microglia toward a disease‐associated
                      state.},
      keywords     = {Amyloid beta-Peptides / Animals / Antibodies, Monoclonal:
                      pharmacology / Cell Line, Tumor / Female / Macrophages /
                      Membrane Glycoproteins: immunology / Mice / Microglia:
                      pathology / Multiple Myeloma / Rats / Rats, Wistar /
                      Receptors, Immunologic: immunology},
      cin          = {AG Haass / Core Technical Staff / AG Tahirovic},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1340007 /
                      I:(DE-2719)1140003},
      pnm          = {341 - Molecular Signaling (POF3-341) / 342 - Disease
                      Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-341 / G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7136959},
      pubmed       = {pmid:32154671},
      doi          = {10.15252/emmm.201911227},
      url          = {https://pub.dzne.de/record/151484},
}