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@ARTICLE{deWeerd:280744,
      author       = {de Weerd, Lis and Hummel, Selina and Müller, Stephan A and
                      Paris, Iñaki and Sandmann, Thomas and Eichholtz, Marie and
                      Gröger, Robin and Englert, Amelie L and Wagner, Stephan and
                      Ha, Connie and Davis, Sonnet S and Warkins, Valerie and Xia,
                      Dan and Nuscher, Brigitte and Berghofer, Anna and Reich,
                      Marvin and Feiten, Astrid Feentje and Schlepckow, Kai and
                      Willem, Michael and Lichtenthaler, Stefan F and Lewcock,
                      Joseph W and Monroe, Kathryn M and Brendel, Matthias and
                      Haass, Christian},
      title        = {{E}arly intervention anti-{A}β immunotherapy attenuates
                      microglial activation without inducing exhaustion at
                      residual plaques.},
      journal      = {Molecular neurodegeneration},
      volume       = {20},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2025-00965},
      pages        = {92},
      year         = {2025},
      abstract     = {Anti-amyloid β-peptide (Aβ) immunotherapy was developed
                      to reduce amyloid plaque pathology and slow cognitive
                      decline during progression of Alzheimer's disease. Efficient
                      amyloid clearance has been proven in clinical trials testing
                      anti-Aβ antibodies, by their impact on cognitive endpoints
                      correlating with the extent of amyloid removal. However,
                      treatment is associated with adverse side effects, such as
                      oedema and haemorrhages, which are potentially linked to the
                      induced immune response. To improve the safety profile of
                      these molecules, it is imperative to understand the
                      consequences of anti-Aβ antibody treatment on immune cell
                      function. Here, we investigated the effects of long-term
                      chronic anti-Aβ treatment on amyloid plaque pathology and
                      microglial response in the APP-SAA triple knock-in mouse
                      model with an intervention paradigm early during
                      amyloidogenesis. Long-term treatment with anti-Aβ results
                      in a robust and dose-dependent lowering of amyloid plaque
                      pathology, with a higher efficiency for reducing diffuse
                      over dense-core plaque deposition. Analysis of the CSF
                      proteome indicates a reduction of markers for
                      neurodegeneration including Tau and α-Synuclein, as well as
                      immune-cell-related proteins. Bulk RNA-seq revealed a
                      dose-dependent attenuation of disease-associated microglial
                      (DAM) and glycolytic gene expression, which is supported by
                      a parallel decrease of glucose uptake and protein levels of
                      Triggering Receptor Expressed on Myeloid cells 2 (Trem2)
                      protein, a major immune receptor involved in DAM activation
                      of microglia. In contrast, DAM activation around residual
                      plaques remains high, regardless of treatment dose. In
                      addition, microglia surrounding residual plaques display a
                      dose-dependent increase in microglial clustering and a
                      selective increase in antigen-presenting and immune
                      signalling proteins. These findings demonstrate that chronic
                      early intervention by an anti-amyloid immunotherapy leads to
                      a dose-dependent decrease in plaque formation, which is
                      associated with lower brain-wide microglial DAM activation
                      and neurodegeneration. Microglia at residual plaques still
                      display a combined DAM and antigen-presenting phenotype that
                      suggests a continued treatment response.},
      keywords     = {Animals / Microglia: metabolism / Microglia: drug effects /
                      Microglia: immunology / Mice / Plaque, Amyloid: pathology /
                      Plaque, Amyloid: metabolism / Plaque, Amyloid: immunology /
                      Amyloid beta-Peptides: immunology / Amyloid beta-Peptides:
                      metabolism / Amyloid beta-Peptides: antagonists $\&$
                      inhibitors / Immunotherapy: methods / Alzheimer Disease:
                      pathology / Alzheimer Disease: metabolism / Alzheimer
                      Disease: immunology / Mice, Transgenic / Disease Models,
                      Animal / Aducanumab (Other) / Alzheimer’s disease (AD)
                      (Other) / Amyloid plaque (Other) / Immunotherapy (Other) /
                      Microglia (Other) / Trem2 (Other) / Amyloid beta-Peptides
                      (NLM Chemicals)},
      cin          = {AG Haass / AG Lichtenthaler},
      ddc          = {570},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40830489},
      doi          = {10.1186/s13024-025-00878-1},
      url          = {https://pub.dzne.de/record/280744},
}