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@ARTICLE{Kummer:163394,
      author       = {Kummer, Markus P. and Ising, Christina and Kummer,
                      Christiane and Sarlus, Heela and Griep, Angelika and
                      Vieira-Saecker, Ana and Schwartz, Stephanie and Halle,
                      Annett and Brückner, Matthias and Händler, Kristian and
                      Schultze, Joachim L and Beyer, Marc-Daniel and Latz, Eicke
                      and Heneka, Michael},
      title        = {{M}icroglial {PD}-1 stimulation by astrocytic {PD}-{L}1
                      suppresses neuroinflammation and {A}lzheimer's disease
                      pathology.},
      journal      = {The EMBO journal},
      volume       = {40},
      number       = {24},
      issn         = {1460-2075},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2022-00156},
      pages        = {e108662},
      year         = {2021},
      abstract     = {Chronic neuroinflammation is a pathogenic component of
                      Alzheimer's disease (AD) that may limit the ability of the
                      brain to clear amyloid deposits and cellular debris. Tight
                      control of the immune system is therefore key to sustain the
                      ability of the brain to repair itself during homeostasis and
                      disease. The immune-cell checkpoint receptor/ligand pair
                      PD-1/PD-L1, known for their inhibitory immune function, is
                      expressed also in the brain. Here, we report upregulated
                      expression of PD-L1 and PD-1 in astrocytes and microglia,
                      respectively, surrounding amyloid plaques in AD patients and
                      in the APP/PS1 AD mouse model. We observed juxtamembrane
                      shedding of PD-L1 from astrocytes, which may mediate
                      ectodomain signaling to PD-1-expressing microglia. Deletion
                      of microglial PD-1 evoked an inflammatory response and
                      compromised amyloid-β peptide (Aβ) uptake. APP/PS1 mice
                      deficient for PD-1 exhibited increased deposition of Aβ,
                      reduced microglial Aβ uptake, and decreased expression of
                      the Aβ receptor CD36 on microglia. Therefore, ineffective
                      immune regulation by the PD-1/PD-L1 axis contributes to Aβ
                      plaque deposition during chronic neuroinflammation in AD.},
      keywords     = {Aged / Aged, 80 and over / Alzheimer Disease: genetics /
                      Alzheimer Disease: immunology / Amyloid beta-Protein
                      Precursor: genetics / Amyloid beta-Protein Precursor:
                      toxicity / Animals / Astrocytes: metabolism / B7-H1 Antigen:
                      metabolism / CD36 Antigens: metabolism / Case-Control
                      Studies / Disease Models, Animal / Female / Gene Deletion /
                      HEK293 Cells / HeLa Cells / Humans / Male / Mice / Mice,
                      Transgenic / Microglia: metabolism / Middle Aged /
                      Programmed Cell Death 1 Receptor: genetics / Programmed Cell
                      Death 1 Receptor: metabolism / Up-Regulation / APP (Other) /
                      PD-1 knockout mice (Other) / PS1 mice (Other) / innate
                      immune system (Other) / microglia (Other) / APP protein,
                      human (NLM Chemicals) / Amyloid beta-Protein Precursor (NLM
                      Chemicals) / B7-H1 Antigen (NLM Chemicals) / CD274 protein,
                      human (NLM Chemicals) / CD36 Antigens (NLM Chemicals) / CD36
                      protein, human (NLM Chemicals) / PDCD1 protein, human (NLM
                      Chemicals) / Programmed Cell Death 1 Receptor (NLM
                      Chemicals)},
      cin          = {Biomarker / AG Heneka / AG Halle / AG Beyer / AG Latz / AG
                      Schultze / PRECISE},
      ddc          = {570},
      cid          = {I:(DE-2719)1011301 / I:(DE-2719)1011303 /
                      I:(DE-2719)1013034 / I:(DE-2719)1013035 / I:(DE-2719)1013024
                      / I:(DE-2719)1013038 / I:(DE-2719)1013031},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 352 -
                      Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351) / 354 - Disease Prevention and Healthy Aging
                      (POF4-354)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352 /
                      G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-354},
      experiment   = {EXP:(DE-2719)PRECISE-20190321},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34825707},
      pmc          = {pmc:PMC8672180},
      doi          = {10.15252/embj.2021108662},
      url          = {https://pub.dzne.de/record/163394},
}