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@ARTICLE{AngladaHuguet:258261,
      author       = {Anglada-Huguet, Marta and Endepols, Heike and Sydow, Astrid
                      and Hilgers, Ronja and Neumaier, Bernd and Drzezga,
                      Alexander and Kaniyappan, Senthilvelrajan and Mandelkow,
                      Eckhard and Mandelkow, Eva-Maria},
      title        = {{R}eversal of {T}au-{D}ependent {C}ognitive {D}ecay by
                      {B}locking {A}denosine {A}1 {R}eceptors: {C}omparison of
                      {T}ransgenic {M}ouse {M}odels with {D}ifferent {L}evels of
                      {T}auopathy.},
      journal      = {International journal of molecular sciences},
      volume       = {24},
      number       = {11},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {DZNE-2023-00607},
      pages        = {9260},
      year         = {2023},
      abstract     = {The accumulation of tau is a hallmark of several
                      neurodegenerative diseases and is associated with neuronal
                      hypoactivity and presynaptic dysfunction. Oral
                      administration of the adenosine A1 receptor antagonist
                      rolofylline (KW-3902) has previously been shown to reverse
                      spatial memory deficits and to normalize the basic synaptic
                      transmission in a mouse line expressing full-length
                      pro-aggregant tau (TauΔK) at low levels, with late onset of
                      disease. However, the efficacy of treatment remained to be
                      explored for cases of more aggressive tauopathy. Using a
                      combination of behavioral assays, imaging with several
                      PET-tracers, and analysis of brain tissue, we compared the
                      curative reversal of tau pathology by blocking adenosine A1
                      receptors in three mouse models expressing different types
                      and levels of tau and tau mutants. We show through positron
                      emission tomography using the tracer [18F]CPFPX (a selective
                      A1 receptor ligand) that intravenous injection of
                      rolofylline effectively blocks A1 receptors in the brain.
                      Moreover, when administered to TauΔK mice, rolofylline can
                      reverse tau pathology and synaptic decay. The beneficial
                      effects are also observed in a line with more aggressive tau
                      pathology, expressing the amyloidogenic repeat domain of tau
                      (TauRDΔK) with higher aggregation propensity. Both models
                      develop a progressive tau pathology with missorting,
                      phosphorylation, accumulation of tau, loss of synapses, and
                      cognitive decline. TauRDΔK causes pronounced
                      neurofibrillary tangle assembly concomitant with neuronal
                      death, whereas TauΔK accumulates only to tau pretangles
                      without overt neuronal loss. A third model tested, the
                      rTg4510 line, has a high expression of mutant TauP301L and
                      hence a very aggressive phenotype starting at ~3 months of
                      age. This line failed to reverse pathology upon rolofylline
                      treatment, consistent with a higher accumulation of
                      tau-specific PET tracers and inflammation. In conclusion,
                      blocking adenosine A1 receptors by rolofylline can reverse
                      pathology if the pathological potential of tau remains below
                      a threshold value that depends on concentration and
                      aggregation propensity.},
      keywords     = {Mice / Animals / Mice, Transgenic / Receptor, Adenosine A1:
                      genetics / Receptor, Adenosine A1: metabolism / tau
                      Proteins: genetics / tau Proteins: metabolism / Hippocampus:
                      metabolism / Tauopathies: drug therapy / Tauopathies:
                      genetics / Tauopathies: metabolism / Cognition / Disease
                      Models, Animal / Alzheimer’s disease (Other) /
                      Alzheimer’s disease (Other) / Alzheimer’s disease
                      (Other) / Alzheimer’s disease (Other) / PET (Other) /
                      adenosine A1 receptor (Other) / behavior (Other) /
                      rolofylline (Other) / synapses (Other) / tau protein (Other)
                      / Receptor, Adenosine A1 (NLM Chemicals) / tau Proteins (NLM
                      Chemicals)},
      cin          = {AG Mandelkow 2 ; AG Mandelkow 2 / AG Mandelkow 1 ; AG
                      Mandelkow 1 / AG Schneider / AG Boecker},
      ddc          = {540},
      cid          = {I:(DE-2719)1013015 / I:(DE-2719)1013014 /
                      I:(DE-2719)1011305 / I:(DE-2719)1011202},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37298211},
      pmc          = {pmc:PMC10252552},
      doi          = {10.3390/ijms24119260},
      url          = {https://pub.dzne.de/record/258261},
}