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Acta Neuropathol. 2015 Nov;130(5):619-31. doi: 10.1007/s00401-015-1483-3. Epub 2015 Oct 6.

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Author information

1
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.
2
Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str. 23, 81377, Munich, Germany.
3
NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany.
4
DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), 37073, Göttingen, Germany.
5
MODAG GmbH, 55324, Wendelsheim, Germany.
6
Neurologie, Universitätsmedizin Göttingen, 37075, Göttingen, Germany.
7
BioMolekulare Optik, Ludwig-Maximilians-Universität, 80538, Munich, Germany.
8
Neurologische Klinik, Klinikum der Ludwig-Maximilians-Universität, Munich, Germany.
9
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany. martin.fuhrmann@dzne.de.

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.

KEYWORDS:

Alzheimer’s disease; Anle138b; Protein aggregation; Tau; Tau aggregation inhibitor; Tauopathy

PMID:
26439832
PMCID:
PMC4612332
DOI:
10.1007/s00401-015-1483-3
[Indexed for MEDLINE]
Free PMC Article

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