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@ARTICLE{Decker:138485,
      author       = {Decker, Jochen Martin and Krüger, Lars and Sydow, Astrid
                      and Dennissen, Frank Ja and Siskova, Zuzana and Mandelkow,
                      Eckhard and Mandelkow, Eva-Maria},
      title        = {{T}he {T}au/{A}152{T} mutation, a risk factor for
                      frontotemporal-spectrum disorders, leads to {NR}2{B}
                      receptor-mediated excitotoxicity.},
      journal      = {EMBO reports},
      volume       = {17},
      number       = {4},
      issn         = {1469-221X},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-04807},
      pages        = {552-569},
      year         = {2016},
      abstract     = {We report on a novel transgenic mouse model expressing
                      human full-length Tau with the Tau mutation A152T
                      (hTau(AT)), a risk factor for FTD-spectrum disorders
                      including PSP and CBD Brain neurons reveal pathological Tau
                      conformation, hyperphosphorylation, mis-sorting,
                      aggregation, neuronal degeneration, and progressive loss,
                      most prominently in area CA3 of the hippocampus. The mossy
                      fiber pathway shows enhanced basal synaptic transmission
                      without changes in short- or long-term plasticity. In
                      organotypic hippocampal slices, extracellular glutamate
                      increases early above control levels, followed by a rise in
                      neurotoxicity. These changes are normalized by inhibiting
                      neurotransmitter release or by blocking voltage-gated sodium
                      channels. CA3 neurons show elevated intracellular calcium
                      during rest and after activity induction which is sensitive
                      to NR2B antagonizing drugs, demonstrating a pivotal role of
                      extrasynaptic NMDA receptors. Slices show pronounced
                      epileptiform activity and axonal sprouting of mossy fibers.
                      Excitotoxic neuronal death is ameliorated by ceftriaxone,
                      which stimulates astrocytic glutamate uptake via the
                      transporter EAAT2/GLT1. In summary, hTau(AT) causes
                      excitotoxicity mediated by NR2B-containing NMDA receptors
                      due to enhanced extracellular glutamate.},
      keywords     = {Animals / CA3 Region, Hippocampal: metabolism / CA3 Region,
                      Hippocampal: pathology / Calcium: metabolism / Culture
                      Media: chemistry / Disease Models, Animal / Frontotemporal
                      Dementia: physiopathology / Glutamic Acid: analysis / Humans
                      / Mice / Mice, Transgenic / Mutation / Neuronal Plasticity /
                      Neurons: chemistry / Neurons: metabolism / Neurons:
                      pathology / Organ Culture Techniques / Receptors,
                      N-Methyl-D-Aspartate: metabolism / Synaptic Transmission /
                      tau Proteins: chemistry / tau Proteins: genetics / tau
                      Proteins: metabolism / Culture Media (NLM Chemicals) / NR2B
                      NMDA receptor (NLM Chemicals) / Receptors,
                      N-Methyl-D-Aspartate (NLM Chemicals) / tau Proteins (NLM
                      Chemicals) / Glutamic Acid (NLM Chemicals) / Calcium (NLM
                      Chemicals)},
      cin          = {AG (Eva) Mandelkow / AG Remy / Tech Transfer / AG (Eckhard)
                      Mandelkow},
      ddc          = {570},
      cid          = {I:(DE-2719)1013015 / I:(DE-2719)1013006 /
                      I:(DE-2719)1030028 / I:(DE-2719)1013014},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 341
                      - Molecular Signaling (POF3-341)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-341},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26931569},
      pmc          = {pmc:PMC4818782},
      doi          = {10.15252/embr.201541439},
      url          = {https://pub.dzne.de/record/138485},
}