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Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice.

Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT - PLoS ONE (2013)

Bottom Line: Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain.The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis.These effects were visible with early preventive or late treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.

ABSTRACT
Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.

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Levels of sarkosyl extracted insoluble tau were significantly reduced in the forebrain of P301S mice after 5 months of long-term rapamycin treatment (R, nā€Š=ā€Š6) when compared to vehicle treated mice (V, nā€Š=ā€Š5) (A, 5MT group; Western blot using BR134 antibody).A comparable lowering of insoluble tau was obtained by late short-term rapamycin administration over 6 weeks (B; 6WT group, nā€Š=ā€Š6/6). In parallel, the accumulation of tau hyperphosphorylated at the AT8 and AT100 epitopes was significantly lowered (C; 6WT group, nā€Š=ā€Š6/6). Quantification of tau Western blots was subjected to unpaired T-tests and T-tests adjusted for unequal variances (Welch-Test), yielding both similar results. *p<0.05 and **p<0.01.
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pone-0062459-g003: Levels of sarkosyl extracted insoluble tau were significantly reduced in the forebrain of P301S mice after 5 months of long-term rapamycin treatment (R, nā€Š=ā€Š6) when compared to vehicle treated mice (V, nā€Š=ā€Š5) (A, 5MT group; Western blot using BR134 antibody).A comparable lowering of insoluble tau was obtained by late short-term rapamycin administration over 6 weeks (B; 6WT group, nā€Š=ā€Š6/6). In parallel, the accumulation of tau hyperphosphorylated at the AT8 and AT100 epitopes was significantly lowered (C; 6WT group, nā€Š=ā€Š6/6). Quantification of tau Western blots was subjected to unpaired T-tests and T-tests adjusted for unequal variances (Welch-Test), yielding both similar results. *p<0.05 and **p<0.01.

Mentions: In parallel to the observed attenuation in cortical tau tangle pathology in the stereological assessment, biochemical analysis revealed a significant reduction of sarkosyl insoluble tau in the forebrain of long- and short-term treated P301S mice (5MT: rapamycin group: percentage of vehicle treated mice: 56.7Ā±17.5%, pā€Š=ā€Š0.03, Fig. 3A; 6WT: 28.0Ā±36.2%, pā€Š=ā€Š0.004, Fig. 3B). Tau hyperphosphorylated at AT8 and AT100 was significantly lowered upon 6 weeks of rapamycin treatment as measured by Western blotting (6WT: rapamycin group: percentage of vehicle treated mice: AT8āˆ¶11.2Ā±42.3%, pā€Š=ā€Š0.004; AT100āˆ¶4.1Ā±17.9%, pā€Š=ā€Š0.04, Fig. 3C). In contrast, no decrease of forebrain soluble tau levels was noted in these aged mice, and no acute suppression of soluble tau protein generation occurred after rapamycin administration in pretangle P301S mice (Fig. S3A). Endogenous murine tau furthermore remained unchanged after acute and chronic rapamycin administration in P301S mice as assessed by the mouse tau specific antibody T49 [22] (Fig. S3B).


Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice.

Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT - PLoS ONE (2013)

Levels of sarkosyl extracted insoluble tau were significantly reduced in the forebrain of P301S mice after 5 months of long-term rapamycin treatment (R, nā€Š=ā€Š6) when compared to vehicle treated mice (V, nā€Š=ā€Š5) (A, 5MT group; Western blot using BR134 antibody).A comparable lowering of insoluble tau was obtained by late short-term rapamycin administration over 6 weeks (B; 6WT group, nā€Š=ā€Š6/6). In parallel, the accumulation of tau hyperphosphorylated at the AT8 and AT100 epitopes was significantly lowered (C; 6WT group, nā€Š=ā€Š6/6). Quantification of tau Western blots was subjected to unpaired T-tests and T-tests adjusted for unequal variances (Welch-Test), yielding both similar results. *p<0.05 and **p<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646815&req=5

pone-0062459-g003: Levels of sarkosyl extracted insoluble tau were significantly reduced in the forebrain of P301S mice after 5 months of long-term rapamycin treatment (R, nā€Š=ā€Š6) when compared to vehicle treated mice (V, nā€Š=ā€Š5) (A, 5MT group; Western blot using BR134 antibody).A comparable lowering of insoluble tau was obtained by late short-term rapamycin administration over 6 weeks (B; 6WT group, nā€Š=ā€Š6/6). In parallel, the accumulation of tau hyperphosphorylated at the AT8 and AT100 epitopes was significantly lowered (C; 6WT group, nā€Š=ā€Š6/6). Quantification of tau Western blots was subjected to unpaired T-tests and T-tests adjusted for unequal variances (Welch-Test), yielding both similar results. *p<0.05 and **p<0.01.
Mentions: In parallel to the observed attenuation in cortical tau tangle pathology in the stereological assessment, biochemical analysis revealed a significant reduction of sarkosyl insoluble tau in the forebrain of long- and short-term treated P301S mice (5MT: rapamycin group: percentage of vehicle treated mice: 56.7Ā±17.5%, pā€Š=ā€Š0.03, Fig. 3A; 6WT: 28.0Ā±36.2%, pā€Š=ā€Š0.004, Fig. 3B). Tau hyperphosphorylated at AT8 and AT100 was significantly lowered upon 6 weeks of rapamycin treatment as measured by Western blotting (6WT: rapamycin group: percentage of vehicle treated mice: AT8āˆ¶11.2Ā±42.3%, pā€Š=ā€Š0.004; AT100āˆ¶4.1Ā±17.9%, pā€Š=ā€Š0.04, Fig. 3C). In contrast, no decrease of forebrain soluble tau levels was noted in these aged mice, and no acute suppression of soluble tau protein generation occurred after rapamycin administration in pretangle P301S mice (Fig. S3A). Endogenous murine tau furthermore remained unchanged after acute and chronic rapamycin administration in P301S mice as assessed by the mouse tau specific antibody T49 [22] (Fig. S3B).

Bottom Line: Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain.The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis.These effects were visible with early preventive or late treatment.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.

ABSTRACT
Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.

Show MeSH
Related in: MedlinePlus