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@ARTICLE{Barth:162710,
      author       = {Barth, Melanie and Bacioglu, Mehtap and Schwarz, Niklas and
                      Novotny, Renata and Brandes, Janine and Welzer, Marc and
                      Mazzitelli, Sonia and Häsler, Lisa and Schweighauser,
                      Manuel and Wuttke, Thomas V and Kronenberg-Versteeg, Deborah
                      and Fog, Karina and Ambjørn, Malene and Alik, Ania and
                      Melki, Ronald and Kahle, Philipp and Shimshek, Derya R and
                      Koch, Henner and Jucker, Mathias and Tanriöver, Gaye},
      title        = {{M}icroglial inclusions and neurofilament light chain
                      release follow neuronal α-synuclein lesions in long-term
                      brain slice cultures.},
      journal      = {Molecular neurodegeneration},
      volume       = {16},
      number       = {1},
      issn         = {1750-1326},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2021-01367},
      pages        = {54},
      year         = {2021},
      note         = {CC BY},
      abstract     = {Proteopathic brain lesions are a hallmark of many
                      age-related neurodegenerative diseases including
                      synucleinopathies and develop at least a decade before the
                      onset of clinical symptoms. Thus, understanding of the
                      initiation and propagation of such lesions is key for
                      developing therapeutics to delay or halt disease
                      progression.Alpha-synuclein (αS) inclusions were induced in
                      long-term murine and human slice cultures by seeded
                      aggregation. An αS seed-recognizing human antibody was
                      tested for blocking seeding and/or spreading of the αS
                      lesions. Release of neurofilament light chain (NfL) into the
                      culture medium was assessed.To study initial stages of
                      α-synucleinopathies, we induced αS inclusions in murine
                      hippocampal slice cultures by seeded aggregation. Induction
                      of αS inclusions in neurons was apparent as early as 1week
                      post-seeding, followed by the occurrence of microglial
                      inclusions in vicinity of the neuronal lesions at 2-3
                      weeks. The amount of αS inclusions was dependent on the
                      type of αS seed and on the culture's genetic background
                      (wildtype vs A53T-αS genotype). Formation of αS inclusions
                      could be monitored by neurofilament light chain protein
                      release into the culture medium, a fluid biomarker of
                      neurodegeneration commonly used in clinical settings. Local
                      microinjection of αS seeds resulted in spreading of αS
                      inclusions to neuronally connected hippocampal subregions,
                      and seeding and spreading could be inhibited by an αS
                      seed-recognizing human antibody. We then applied parameters
                      of the murine cultures to surgical resection-derived adult
                      human long-term neocortical slice cultures from 22 to
                      61-year-old donors. Similarly, in these human slice
                      cultures, proof-of-principle induction of αS lesions was
                      achieved at 1week post-seeding in combination with viral
                      A53T-αS expressions.The successful translation of these
                      brain cultures from mouse to human with the first reported
                      induction of human αS lesions in a true adult human brain
                      environment underlines the potential of this model to study
                      proteopathic lesions in intact mouse and now even aged human
                      brain environments.},
      keywords     = {Animals / Humans / Inclusion Bodies: pathology / Mice /
                      Microglia: metabolism / Microglia: pathology / Neurofilament
                      Proteins: metabolism / Neurons: metabolism / Neurons:
                      pathology / Organ Culture Techniques: methods /
                      Synucleinopathies / alpha-Synuclein: toxicity /
                      Alpha-synuclein (Other) / Microglia (Other) / Neurofilament
                      light chain (Other) / Slice culture (Other)},
      cin          = {AG Jucker / AG Heutink / AG Kahle},
      ddc          = {570},
      cid          = {I:(DE-2719)1210001 / I:(DE-2719)1210002 /
                      I:(DE-2719)1210000-4},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 354 - Disease
                      Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34380535},
      pmc          = {pmc:PMC8356412},
      doi          = {10.1186/s13024-021-00471-2},
      url          = {https://pub.dzne.de/record/162710},
}