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@ARTICLE{FerreiraRodrigues:266329,
      author       = {Ferreira Rodrigues, Sara and Anglada-Huguet, Marta and
                      Hochgräfe, Katja and Kaniyappan, Senthilvelrajan and
                      Wegmann, Susanne and Mandelkow, Eva Maria},
      title        = {{S}preading of {T}au {P}rotein {D}oes {N}ot {D}epend on
                      {A}ggregation {P}ropensity.},
      journal      = {Journal of molecular neuroscience},
      volume       = {73},
      number       = {9-10},
      issn         = {0895-8696},
      address      = {New York, NY},
      publisher    = {Springer},
      reportid     = {DZNE-2023-01118},
      pages        = {693 - 712},
      year         = {2023},
      abstract     = {The stereotypical progression of Tau pathology during
                      Alzheimer disease has been attributed to trans-neuronal
                      spreading of misfolded Tau proteins, followed by prion-like
                      templated aggregation of Tau. The nature of Tau and the
                      cellular mechanisms of Tau spreading are still under debate.
                      We hypothesized that Tau's propensity for aggregation would
                      correlate with its ability to spread across synapses and
                      propagate pathology. To study the progressive propagation of
                      Tau proteins in brain regions relevant for Alzheimer
                      disease, we used mice expressing near-physiological levels
                      of full-length human Tau protein carrying pro-aggregant
                      (TauΔK280, TauΔK) or anti-aggregant (TauΔK280-PP,
                      TauΔK-PP) mutations in the entorhinal cortex (EC). To
                      enhance Tau expression in the EC, we performed EC injections
                      of adeno-associated virus (AAV) particles encoding TauΔK or
                      TauΔK-PP. The brains of injected and non-injected EC/TauΔK
                      and EC/TauΔK-PP mice were studied by immunohistological and
                      biochemical techniques to detect Tau propagation to dentate
                      gyrus (DG) neurons and Tau-induced pathological changes.
                      Pro- and anti-aggregant mice had comparable low transgene
                      expression (~0.2 times endogenous mouse Tau). They
                      accumulated human Tau at similar rates and only in
                      expressing EC neurons, including their axonal projections of
                      the perforant path and presynaptic terminals in the
                      molecular layer of the DG. Pro-aggregant EC/TauΔK mice
                      showed misfolded Tau and synaptic protein alterations in EC
                      neurons, not observed in anti-aggregant EC/TauΔK-PP mice.
                      Additional AAV-mediated expression of TauΔK or TauΔK-PP in
                      EC/TauΔK or EC/TauΔK-PP mice, respectively, increased the
                      human Tau expression to ~0.65 times endogenous mouse Tau,
                      with comparable spreading of TauΔK and TauΔK-PP throughout
                      the EC. There was a low level of transcellular propagation
                      of Tau protein, without pathological phosphorylation or
                      misfolding, as judged by diagnostic antibodies.
                      Additionally, TauΔK but not TauΔK-PP expression induced
                      hippocampal astrogliosis. Low levels of pro- or
                      anti-aggregant full-length Tau show equivalent distributions
                      in EC neurons, independent of their aggregation propensity.
                      Increasing the expression via AAV induce local Tau
                      misfolding in the EC neurons, synaptotoxicity, and
                      astrogliosis and lead to a low level of detectable
                      trans-neuronal spreading of Tau. This depends on its
                      concentration in the EC, but, contrary to expectations, does
                      not depend on Tau's aggregation propensity/misfolding and
                      does not lead to templated misfolding in recipient neurons.},
      keywords     = {Mice / Animals / Humans / tau Proteins: genetics / tau
                      Proteins: metabolism / Alzheimer Disease: genetics /
                      Tauopathies: metabolism / Gliosis / Hippocampus: metabolism
                      / Disease Models, Animal / Mice, Transgenic / Aggregation
                      propensity (Other) / Alzheimer disease (Other) /
                      Neuroinflammation (Other) / Tau pathology (Other) / Tau
                      spreading (Other) / tau Proteins (NLM Chemicals)},
      cin          = {AG Mandelkow 2 / AG Schneider / AG Wegmann},
      ddc          = {610},
      cid          = {I:(DE-2719)1013015 / I:(DE-2719)1011305 /
                      I:(DE-2719)1810006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37606769},
      pmc          = {pmc:PMC10694122},
      doi          = {10.1007/s12031-023-02143-w},
      url          = {https://pub.dzne.de/record/266329},
}