title: Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.
abstract: Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Wagner
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Krauss
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 23, 81377, Munich, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Shi
authors.affiliation: NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073, Göttingen, Germany.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryazanov
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Steffen
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Miklitz
authors.affiliation: NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073, Göttingen, Germany.|MODAG GmbH, 55324, Wendelsheim, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Leonov
authors.affiliation: Neurologie, Universitätsmedizin Göttingen, 37075, Göttingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kleinknecht
authors.affiliation: Neurologie, Universitätsmedizin Göttingen, 37075, Göttingen, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Göricke
authors.affiliation: Neurologie, Universitätsmedizin Göttingen, 37075, Göttingen, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: MODAG GmbH, 55324, Wendelsheim, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weckbecker
authors.affiliation: BioMolekulare Optik, Ludwig-Maximilians-Universität, 80538, Munich, Germany.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Reiner
authors.affiliation: BioMolekulare Optik, Ludwig-Maximilians-Universität, 80538, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zinth
authors.affiliation: Neurologische Klinik, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Ehninger
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Remy
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 23, 81377, Munich, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.affiliation: NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073, Göttingen, Germany.|MODAG GmbH, 55324, Wendelsheim, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 23, 81377, Munich, Germany.|MODAG GmbH, 55324, Wendelsheim, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. martin.fuhrmann@dzne.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Fuhrmann
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D024801:Tauopathies / Q000188:drug therapy* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C000593290:3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole; D052117:Benzodioxoles; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D011720:Pyrazoles; D016875:tau Proteins
keywords: Alzheimer’s disease; Anle138b; Protein aggregation; Tau; Tau aggregation inhibitor; Tauopathy