TY  - JOUR
AU  - Wagner, Jens
AU  - Krauß, Sybille
AU  - Shi, Song
AU  - Ryazanov, Sergey
AU  - Steffen, Julia
AU  - Miklitz, Carolin
AU  - Leonov, Andrei
AU  - Kleinknecht, Alexander
AU  - Göricke, Bettina
AU  - Weishaupt, Jochen H
AU  - Weckbecker, Daniel
AU  - Reiner, Anne M
AU  - Zinth, Wolfgang
AU  - Levin, Johannes
AU  - Ehninger, Dan
AU  - Remy, Stefan
AU  - Kretzschmar, Hans A
AU  - Griesinger, Christian
AU  - Giese, Armin
AU  - Fuhrmann, Martin
TI  - Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.
JO  - Acta neuropathologica
VL  - 130
IS  - 5
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-04503
SP  - 619-631
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Benzodioxoles: pharmacology
KW  - Cell Death: drug effects
KW  - Cell Death: physiology
KW  - Disease Models, Animal
KW  - Disease Progression
KW  - Female
KW  - Gliosis: drug therapy
KW  - Gliosis: pathology
KW  - Gliosis: physiopathology
KW  - Hippocampus: drug effects
KW  - Hippocampus: pathology
KW  - Hippocampus: physiopathology
KW  - Male
KW  - Mice, Transgenic
KW  - Motor Activity: drug effects
KW  - Motor Activity: physiology
KW  - Neurons: drug effects
KW  - Neurons: pathology
KW  - Neurons: physiology
KW  - Neuroprotective Agents: pharmacology
KW  - Protein Aggregates: drug effects
KW  - Pyrazoles: pharmacology
KW  - Random Allocation
KW  - Recognition, Psychology: drug effects
KW  - Recognition, Psychology: physiology
KW  - Tauopathies: drug therapy
KW  - Tauopathies: pathology
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - 3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole (NLM Chemicals)
KW  - Benzodioxoles (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Mapt protein, mouse (NLM Chemicals)
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - Protein Aggregates (NLM Chemicals)
KW  - Pyrazoles (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26439832
C2  - pmc:PMC4612332
DO  - DOI:10.1007/s00401-015-1483-3
UR  - https://pub.dzne.de/record/138181
ER  -