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

Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J, Miklitz C, Leonov A, Kleinknecht A, Göricke B, Weishaupt JH, Weckbecker D, Reiner AM, Zinth W, Levin J, Ehninger D, Remy S, Kretzschmar HA, Griesinger C, Giese A, Fuhrmann M - Acta Neuropathol. (2015)

Bottom Line: Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo.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.

View Article: PubMed Central - PubMed

Affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Anle138b treatment ameliorates neuropathology of PS19 mice NeuN staining (a) and quantification (b) of the hippocampal CA3 region of ntg, untreated and anle138b-treated PS19 mice. Staining with the synaptic marker synaptophysin in the stratum lucidum (c) and quantification (d) of ntg, untreated and anle138b-treated PS19 mice. Microglia Iba1 and astrocyte GFAP staining (e, g) and quantification (f, h) of ntg and PS19 mice treated and untreated with anle138b. a–h (n = 8–9 PS19 mice/group; n = 4–5 ntg mice/group; 10–12 months). Scale bars 25 µm. Asterisks indicate significant differences relative to untreated PS19 mice (*p < 0.05; **p < 0.01; ***p < 0.001; two-way ANOVA with Bonferroni’s multiple-comparisons test)
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Fig4: Anle138b treatment ameliorates neuropathology of PS19 mice NeuN staining (a) and quantification (b) of the hippocampal CA3 region of ntg, untreated and anle138b-treated PS19 mice. Staining with the synaptic marker synaptophysin in the stratum lucidum (c) and quantification (d) of ntg, untreated and anle138b-treated PS19 mice. Microglia Iba1 and astrocyte GFAP staining (e, g) and quantification (f, h) of ntg and PS19 mice treated and untreated with anle138b. a–h (n = 8–9 PS19 mice/group; n = 4–5 ntg mice/group; 10–12 months). Scale bars 25 µm. Asterisks indicate significant differences relative to untreated PS19 mice (*p < 0.05; **p < 0.01; ***p < 0.001; two-way ANOVA with Bonferroni’s multiple-comparisons test)

Mentions: In Alzheimer’s disease, tau pathology correlates with synapse and neuron loss [23, 33]. PS19 mice recapitulate synapse and neuron loss in the hippocampal CA3 region [50]. Therefore, we quantified the area of NeuN-positive neurons in this brain region at 10–12 months of age. NeuN-immunoreactivity was unchanged comparing anle138b-treated with untreated ntg mice (Fig. 4a, b). In PS19 mice, anle138b treatment significantly ameliorated neuronal loss (Fig. 4a, b). Next, we analyzed synaptic density in the stratum lucidum adjacent to the CA3 region, by immunohistochemical quantification of the marker synaptophysin. Untreated and anle138b-treated ntg littermates exhibited unchanged synapse density. However, untreated PS19 mice lost 55 % of synapses in stratum lucidum that was ameliorated by anle138b (Fig. 4c, d).Fig. 4


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

Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J, Miklitz C, Leonov A, Kleinknecht A, Göricke B, Weishaupt JH, Weckbecker D, Reiner AM, Zinth W, Levin J, Ehninger D, Remy S, Kretzschmar HA, Griesinger C, Giese A, Fuhrmann M - Acta Neuropathol. (2015)

Anle138b treatment ameliorates neuropathology of PS19 mice NeuN staining (a) and quantification (b) of the hippocampal CA3 region of ntg, untreated and anle138b-treated PS19 mice. Staining with the synaptic marker synaptophysin in the stratum lucidum (c) and quantification (d) of ntg, untreated and anle138b-treated PS19 mice. Microglia Iba1 and astrocyte GFAP staining (e, g) and quantification (f, h) of ntg and PS19 mice treated and untreated with anle138b. a–h (n = 8–9 PS19 mice/group; n = 4–5 ntg mice/group; 10–12 months). Scale bars 25 µm. Asterisks indicate significant differences relative to untreated PS19 mice (*p < 0.05; **p < 0.01; ***p < 0.001; two-way ANOVA with Bonferroni’s multiple-comparisons test)
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Related In: Results  -  Collection

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Fig4: Anle138b treatment ameliorates neuropathology of PS19 mice NeuN staining (a) and quantification (b) of the hippocampal CA3 region of ntg, untreated and anle138b-treated PS19 mice. Staining with the synaptic marker synaptophysin in the stratum lucidum (c) and quantification (d) of ntg, untreated and anle138b-treated PS19 mice. Microglia Iba1 and astrocyte GFAP staining (e, g) and quantification (f, h) of ntg and PS19 mice treated and untreated with anle138b. a–h (n = 8–9 PS19 mice/group; n = 4–5 ntg mice/group; 10–12 months). Scale bars 25 µm. Asterisks indicate significant differences relative to untreated PS19 mice (*p < 0.05; **p < 0.01; ***p < 0.001; two-way ANOVA with Bonferroni’s multiple-comparisons test)
Mentions: In Alzheimer’s disease, tau pathology correlates with synapse and neuron loss [23, 33]. PS19 mice recapitulate synapse and neuron loss in the hippocampal CA3 region [50]. Therefore, we quantified the area of NeuN-positive neurons in this brain region at 10–12 months of age. NeuN-immunoreactivity was unchanged comparing anle138b-treated with untreated ntg mice (Fig. 4a, b). In PS19 mice, anle138b treatment significantly ameliorated neuronal loss (Fig. 4a, b). Next, we analyzed synaptic density in the stratum lucidum adjacent to the CA3 region, by immunohistochemical quantification of the marker synaptophysin. Untreated and anle138b-treated ntg littermates exhibited unchanged synapse density. However, untreated PS19 mice lost 55 % of synapses in stratum lucidum that was ameliorated by anle138b (Fig. 4c, d).Fig. 4

Bottom Line: Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo.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.

View Article: PubMed Central - PubMed

Affiliation: German Center for Neurodegenerative Diseases (DZNE), Ludwig-Erhard-Allee 2, 53175, Bonn, Germany.

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.

No MeSH data available.


Related in: MedlinePlus