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@ARTICLE{Unger:154223,
      author       = {Unger, M. S. and Li, E. and Scharnagl, L. and Poupardin, R.
                      and Altendorfer, B. and Mrowetz, H. and Hutter-Paier, B. and
                      Weiger, T. M. and Heneka, Michael and Attems, J. and Aigner,
                      L.},
      title        = {{CD}8+ {T}-cells infiltrate {A}lzheimer’s disease brains
                      and regulate neuronal- and synapse-related gene expression
                      in {APP}-{PS}1 transgenic mice},
      journal      = {Brain, behavior and immunity},
      volume       = {89},
      issn         = {0889-1591},
      address      = {Orlando, Fla.},
      publisher    = {Academic Press},
      reportid     = {DZNE-2021-00084},
      pages        = {67 - 86},
      year         = {2020},
      abstract     = {Neuroinflammation is a major contributor to disease
                      progression in Alzheimer’s disease (AD) and is
                      characterized by the activity of brain resident glial cells,
                      in particular microglia cells. However, there is increasing
                      evidence that peripheral immune cells infiltrate the brain
                      at certain stages of AD progression and shape disease
                      pathology. We recently identified CD8+ T-cells in the brain
                      parenchyma of APP-PS1 transgenic mice being tightly
                      associated with microglia as well as with neuronal
                      structures. The functional role of CD8+ T-cells in the AD
                      brain is however completely unexplored. Here, we demonstrate
                      increased numbers of intra-parenchymal CD8+ T-cells in human
                      AD post-mortem hippocampus, which was replicated in APP-PS1
                      mice. Also, aged WT mice show a remarkable infiltration of
                      CD8+ T-cells, which was more pronounced and had an earlier
                      onset in APP-PS1 mice. To address their functional relevance
                      in AD, we successfully ablated the pool of CD8+ T-cells in
                      the blood, spleen and brain from 12 months-old APP-PS1 and
                      WT mice for a total of 4 weeks using an anti-CD8 antibody
                      treatment. While the treatment at this time of disease stage
                      did neither affect the cognitive outcome nor plaque
                      pathology, RNAseq analysis of the hippocampal transcriptome
                      from APP-PS1 mice lacking CD8+ T-cells revealed highly
                      altered neuronal- and synapse-related gene expression
                      including an up-regulation for neuronal immediate early
                      genes (IEGs) such as the Activity Regulated Cytoskeleton
                      Associated Protein (Arc) and the Neuronal PAS Domain Protein
                      4 (Npas4). Gene ontology enrichment analysis illustrated
                      that the biological processes “regulation of neuronal
                      synaptic plasticity” and the cellular components
                      “postsynapses” were over-represented upon CD8+ T-cell
                      ablation. Additionally, Kegg pathway analysis showed
                      up-regulated pathways for “calcium signaling”,
                      “long-term potentiation”, “glutamatergic synapse”
                      and “axon guidance”. Therefore, we conclude that CD8+
                      T-cells infiltrate the aged and AD brain and that brain CD8+
                      T-cells might directly contribute to neuronal dysfunction in
                      modulating synaptic plasticity. Further analysis will be
                      essential to uncover the exact mechanism of how CD8+ T-cells
                      modulate the neuronal landscape and thereby contribute to AD
                      pathology.},
      keywords     = {Alzheimer Disease: genetics / Amyloid beta-Peptides:
                      metabolism / Amyloid beta-Protein Precursor: genetics /
                      Amyloid beta-Protein Precursor: metabolism / Animals /
                      Brain: metabolism / CD8-Positive T-Lymphocytes: metabolism /
                      Disease Models, Animal / Gene Expression / Mice / Mice,
                      Transgenic / Presenilin-1: genetics / Synapses: metabolism},
      cin          = {AG Heneka 2},
      ddc          = {150},
      cid          = {I:(DE-2719)1011303},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32479993},
      doi          = {10.1016/j.bbi.2020.05.070},
      url          = {https://pub.dzne.de/record/154223},
}