Limits...
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

Effect of anle138b treatment on survival and behavior in PS19 transgenic mice a Kaplan–Meier plots of PS19 transgenic and ntg mice. Anle138b treatment significantly prolonged survival time of PS19 mice (**p < 0.01; n = 37 mice/group; Log-Rank test) and attenuated 12-month survival rate compared with untreated PS19 littermates (p < 0.01, Log-Rank test). b Learning and memory were analyzed at 9 months of age using an object–place recognition task. Gray line indicates chance level. Untreated PS19 mice did not show significantly higher exploration of the object in the novel location relative to the object in the known location (discrimination ratio n.s.), which is consistent with memory impairments. In contrast, Anle138b-treated PS19 mice spent significantly more time exploring the object in the novel location, indicating that treatment restored learning and memory in PS19 mice (**p < 0.01; ***p < 0.001; n = 19–24 mice/group; Significantly different from a hypothetical 0.50, one-sample t test). c Total distance traveled in the open-field test was similar in untreated and anle138b-treated mice independent of the genotype, indicating that motor behavior was unaffected in these animals (n = 19–24 mice/group)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4612332&req=5

Fig5: Effect of anle138b treatment on survival and behavior in PS19 transgenic mice a Kaplan–Meier plots of PS19 transgenic and ntg mice. Anle138b treatment significantly prolonged survival time of PS19 mice (**p < 0.01; n = 37 mice/group; Log-Rank test) and attenuated 12-month survival rate compared with untreated PS19 littermates (p < 0.01, Log-Rank test). b Learning and memory were analyzed at 9 months of age using an object–place recognition task. Gray line indicates chance level. Untreated PS19 mice did not show significantly higher exploration of the object in the novel location relative to the object in the known location (discrimination ratio n.s.), which is consistent with memory impairments. In contrast, Anle138b-treated PS19 mice spent significantly more time exploring the object in the novel location, indicating that treatment restored learning and memory in PS19 mice (**p < 0.01; ***p < 0.001; n = 19–24 mice/group; Significantly different from a hypothetical 0.50, one-sample t test). c Total distance traveled in the open-field test was similar in untreated and anle138b-treated mice independent of the genotype, indicating that motor behavior was unaffected in these animals (n = 19–24 mice/group)

Mentions: The high bioavailability of anle138b (Suppl. Fig. 2) allowed treating mice with the drug provided in food pellets. This convenient way of drug application further enabled us to treat mice for a time-period up to 17 months. Non-transgenic mice tolerated such a long treatment very well, since they did not show any change in survival compared to untreated mice (Fig. 5a). Like FTDP-17 patients that carry a P301S tau mutation [12, 32], PS19 mice showed accelerated mortality and 80 % of the mice died within 12 months (Fig. 5a). We tested the effect of anle138b on survival and recognition memory in PS19 animals. By 12 months of age, the absolute survival rate of anle138b-treated PS19 mice was 2.9 times higher than for untreated animals (p < 0.01; survival rates: untreated 16 %; anle138b 46 %; Fig. 5). Moreover, anle138b significantly prolonged the mean survival time of PS19 mice by almost 6 weeks (Fig. 5a; Anle138b: 362 ± 12 days vs. untreated: 321 ± 10 days; n = 37 mice/group; p < 0.05 t test). In addition, the rate of decline for mouse weight after onset of disease was significantly higher in untreated PS19 compared to anle138b-treated PS19 mice (Suppl. Fig. 7). Anle138b had no influence on survival of ntg animals (Fig. 5a). Thus, PS19 mice treated with anle138b showed an increased 12 months absolute survival rate and a prolonged mean survival time.Fig. 5


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)

Effect of anle138b treatment on survival and behavior in PS19 transgenic mice a Kaplan–Meier plots of PS19 transgenic and ntg mice. Anle138b treatment significantly prolonged survival time of PS19 mice (**p < 0.01; n = 37 mice/group; Log-Rank test) and attenuated 12-month survival rate compared with untreated PS19 littermates (p < 0.01, Log-Rank test). b Learning and memory were analyzed at 9 months of age using an object–place recognition task. Gray line indicates chance level. Untreated PS19 mice did not show significantly higher exploration of the object in the novel location relative to the object in the known location (discrimination ratio n.s.), which is consistent with memory impairments. In contrast, Anle138b-treated PS19 mice spent significantly more time exploring the object in the novel location, indicating that treatment restored learning and memory in PS19 mice (**p < 0.01; ***p < 0.001; n = 19–24 mice/group; Significantly different from a hypothetical 0.50, one-sample t test). c Total distance traveled in the open-field test was similar in untreated and anle138b-treated mice independent of the genotype, indicating that motor behavior was unaffected in these animals (n = 19–24 mice/group)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4612332&req=5

Fig5: Effect of anle138b treatment on survival and behavior in PS19 transgenic mice a Kaplan–Meier plots of PS19 transgenic and ntg mice. Anle138b treatment significantly prolonged survival time of PS19 mice (**p < 0.01; n = 37 mice/group; Log-Rank test) and attenuated 12-month survival rate compared with untreated PS19 littermates (p < 0.01, Log-Rank test). b Learning and memory were analyzed at 9 months of age using an object–place recognition task. Gray line indicates chance level. Untreated PS19 mice did not show significantly higher exploration of the object in the novel location relative to the object in the known location (discrimination ratio n.s.), which is consistent with memory impairments. In contrast, Anle138b-treated PS19 mice spent significantly more time exploring the object in the novel location, indicating that treatment restored learning and memory in PS19 mice (**p < 0.01; ***p < 0.001; n = 19–24 mice/group; Significantly different from a hypothetical 0.50, one-sample t test). c Total distance traveled in the open-field test was similar in untreated and anle138b-treated mice independent of the genotype, indicating that motor behavior was unaffected in these animals (n = 19–24 mice/group)
Mentions: The high bioavailability of anle138b (Suppl. Fig. 2) allowed treating mice with the drug provided in food pellets. This convenient way of drug application further enabled us to treat mice for a time-period up to 17 months. Non-transgenic mice tolerated such a long treatment very well, since they did not show any change in survival compared to untreated mice (Fig. 5a). Like FTDP-17 patients that carry a P301S tau mutation [12, 32], PS19 mice showed accelerated mortality and 80 % of the mice died within 12 months (Fig. 5a). We tested the effect of anle138b on survival and recognition memory in PS19 animals. By 12 months of age, the absolute survival rate of anle138b-treated PS19 mice was 2.9 times higher than for untreated animals (p < 0.01; survival rates: untreated 16 %; anle138b 46 %; Fig. 5). Moreover, anle138b significantly prolonged the mean survival time of PS19 mice by almost 6 weeks (Fig. 5a; Anle138b: 362 ± 12 days vs. untreated: 321 ± 10 days; n = 37 mice/group; p < 0.05 t test). In addition, the rate of decline for mouse weight after onset of disease was significantly higher in untreated PS19 compared to anle138b-treated PS19 mice (Suppl. Fig. 7). Anle138b had no influence on survival of ntg animals (Fig. 5a). Thus, PS19 mice treated with anle138b showed an increased 12 months absolute survival rate and a prolonged mean survival time.Fig. 5

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