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@ARTICLE{Zempel:137121,
      author       = {Zempel, Hans and Luedtke, Julia and Kumar, Yatender and
                      Biernat, Jacek and Dawson, Hana and Mandelkow, Eckhard and
                      Mandelkow, Eva-Maria},
      title        = {{A}myloid-β oligomers induce synaptic damage via
                      {T}au-dependent microtubule severing by {TTLL}6 and
                      spastin.},
      journal      = {The EMBO journal},
      volume       = {32},
      number       = {22},
      issn         = {0261-4189},
      address      = {Hoboken, NJ [u.a.]},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-03443},
      pages        = {2920-2937},
      year         = {2013},
      abstract     = {Mislocalization and aggregation of Aβ and Tau combined
                      with loss of synapses and microtubules (MTs) are hallmarks
                      of Alzheimer disease. We exposed mature primary neurons to
                      Aβ oligomers and analysed changes in the Tau/MT system. MT
                      breakdown occurs in dendrites invaded by Tau (Tau
                      missorting) and is mediated by spastin, an MT-severing
                      enzyme. Spastin is recruited by MT polyglutamylation,
                      induced by Tau missorting triggered translocalization of
                      TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites.
                      Consequences are spine loss and mitochondria and
                      neurofilament mislocalization. Missorted Tau is not axonally
                      derived, as shown by axonal retention of photoconvertible
                      Dendra2-Tau, but newly synthesized. Recovery from Aβ insult
                      occurs after Aβ oligomers lose their toxicity and requires
                      the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In
                      neurons derived from Tau-knockout mice, MTs and synapses are
                      resistant to Aβ toxicity because TTLL6 mislocalization and
                      MT polyglutamylation are prevented; hence no spastin
                      recruitment and no MT breakdown occur, enabling faster
                      recovery. Reintroduction of Tau re-establishes Aβ-induced
                      toxicity in TauKO neurons, which requires phosphorylation of
                      Tau's KXGS motifs. Transgenic mice overexpressing Tau show
                      TTLL6 translocalization into dendrites and decreased MT
                      stability. The results provide a rationale for MT
                      stabilization as a therapeutic approach.},
      keywords     = {Adenosine Triphosphatases: physiology / Amyloid
                      beta-Peptides: chemistry / Amyloid beta-Peptides: physiology
                      / Animals / Cells, Cultured / Glutamic Acid: metabolism /
                      Mice / Mice, Knockout / Microtubules: physiology / Peptide
                      Synthases: physiology / Rats / Spastin / Synapses: pathology
                      / tau Proteins: genetics / tau Proteins: physiology /
                      Amyloid beta-Peptides (NLM Chemicals) / Mapt protein, mouse
                      (NLM Chemicals) / tau Proteins (NLM Chemicals) / Glutamic
                      Acid (NLM Chemicals) / Adenosine Triphosphatases (NLM
                      Chemicals) / Spastin (NLM Chemicals) / Spast protein, mouse
                      (NLM Chemicals) / Peptide Synthases (NLM Chemicals) / TTLL6
                      protein, mouse (NLM Chemicals)},
      cin          = {AG Mandelkow 1 / AG Mandelkow 2},
      ddc          = {570},
      cid          = {I:(DE-2719)1013014 / I:(DE-2719)1013015},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24065130},
      pmc          = {pmc:PMC3831312},
      doi          = {10.1038/emboj.2013.207},
      url          = {https://pub.dzne.de/record/137121},
}