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Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV - Aging (Albany NY) (2013)

Bottom Line: Rapamycin decreased the percentage of animals with demyelination and the number of loci.Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity.We conclude that rapamycin in low chronic doses can suppress brain aging.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cytology and Genetics SB RAS, Acad. , 630090, Novosibirsk, Russia. gorislavna@mail.ru

ABSTRACT
Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

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Effect of rapamycin (0.5 mg/kg per day) on Tau, Tau phospho T181 and APP in the hippocampus of OXYS and Wistar rats (n=6). A: Levels of App by immunoblot. B: Levels of total Tau. C: Levels of Tau phospho T181. D: Representative immunoblots of App, Tau and Tau phosphor T181 in the hippocampus of OXYS and Wistar rat. * -P < 0.05, statistically significant effect of rapamycin; #−P < 0.05 between OXYS and Wistar rats. Data are presented as mean ± SEM.
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Figure 3: Effect of rapamycin (0.5 mg/kg per day) on Tau, Tau phospho T181 and APP in the hippocampus of OXYS and Wistar rats (n=6). A: Levels of App by immunoblot. B: Levels of total Tau. C: Levels of Tau phospho T181. D: Representative immunoblots of App, Tau and Tau phosphor T181 in the hippocampus of OXYS and Wistar rat. * -P < 0.05, statistically significant effect of rapamycin; #−P < 0.05 between OXYS and Wistar rats. Data are presented as mean ± SEM.

Mentions: We next studied the effect of rapamycin on the β-amyloid cascade as the target for the treatment of neurodegenerative diseases. Immunoblot analysis of soluble hippocampus homogenates revealed that the Aβ protein level in hippocampus was not affected by genotype (F1,12=0.52, p>0.47) or rapamicyn (F1,12=0.69, p<0.42). There was no difference between APP in 3-month-old OXYS and Wistar rats (Fig. 3). The level of total Tau in the rats was dependent on genotype (F1,18=10.2; p <0.003): in OXYS rats, it was 20 percent higher than in Wistar (p<0.003). Rapamycin significantly decreased Tau in hippocampus OXYS and Wistar rats (p<0.001 and p<0.001, respectively). Tau phosphorylation (T181) in OXYS rats was higher than in Wistar rats (p<0.017). Treatment with rapamycin induced a progressive reduction Tau phosphorylation in OXYS and Wistar rats (p<0.001 and p<0.002) (Fig. 3).


Rapamycin suppresses brain aging in senescence-accelerated OXYS rats.

Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV - Aging (Albany NY) (2013)

Effect of rapamycin (0.5 mg/kg per day) on Tau, Tau phospho T181 and APP in the hippocampus of OXYS and Wistar rats (n=6). A: Levels of App by immunoblot. B: Levels of total Tau. C: Levels of Tau phospho T181. D: Representative immunoblots of App, Tau and Tau phosphor T181 in the hippocampus of OXYS and Wistar rat. * -P < 0.05, statistically significant effect of rapamycin; #−P < 0.05 between OXYS and Wistar rats. Data are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824413&req=5

Figure 3: Effect of rapamycin (0.5 mg/kg per day) on Tau, Tau phospho T181 and APP in the hippocampus of OXYS and Wistar rats (n=6). A: Levels of App by immunoblot. B: Levels of total Tau. C: Levels of Tau phospho T181. D: Representative immunoblots of App, Tau and Tau phosphor T181 in the hippocampus of OXYS and Wistar rat. * -P < 0.05, statistically significant effect of rapamycin; #−P < 0.05 between OXYS and Wistar rats. Data are presented as mean ± SEM.
Mentions: We next studied the effect of rapamycin on the β-amyloid cascade as the target for the treatment of neurodegenerative diseases. Immunoblot analysis of soluble hippocampus homogenates revealed that the Aβ protein level in hippocampus was not affected by genotype (F1,12=0.52, p>0.47) or rapamicyn (F1,12=0.69, p<0.42). There was no difference between APP in 3-month-old OXYS and Wistar rats (Fig. 3). The level of total Tau in the rats was dependent on genotype (F1,18=10.2; p <0.003): in OXYS rats, it was 20 percent higher than in Wistar (p<0.003). Rapamycin significantly decreased Tau in hippocampus OXYS and Wistar rats (p<0.001 and p<0.001, respectively). Tau phosphorylation (T181) in OXYS rats was higher than in Wistar rats (p<0.017). Treatment with rapamycin induced a progressive reduction Tau phosphorylation in OXYS and Wistar rats (p<0.001 and p<0.002) (Fig. 3).

Bottom Line: Rapamycin decreased the percentage of animals with demyelination and the number of loci.Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity.We conclude that rapamycin in low chronic doses can suppress brain aging.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cytology and Genetics SB RAS, Acad. , 630090, Novosibirsk, Russia. gorislavna@mail.ru

ABSTRACT
Cellular and organismal aging are driven in part by the MTOR (mechanistic target of rapamycin) pathway and rapamycin extends life span inC elegans, Drosophila and mice. Herein, we investigated effects of rapamycin on brain aging in OXYS rats. Previously we found, in OXYS rats, an early development of age-associated pathological phenotypes similar to several geriatric disorders in humans, including cerebral dysfunctions. Behavioral alterations as well as learning and memory deficits develop by 3 months. Here we show that rapamycin treatment (0.1 or 0.5 mg/kg as a food mixture daily from the age of 1.5 to 3.5 months) decreased anxiety and improved locomotor and exploratory behavior in OXYS rats. In untreated OXYS rats, MRI revealed an increase of the area of hippocampus, substantial hydrocephalus and 2-fold increased area of the lateral ventricles. Rapamycin treatment prevented these abnormalities, erasing the difference between OXYS and Wister rats (used as control). All untreated OXYS rats showed signs of neurodegeneration, manifested by loci of demyelination. Rapamycin decreased the percentage of animals with demyelination and the number of loci. Levels of Tau and phospho-Tau (T181) were increased in OXYS rats (compared with Wistar). Rapamycin significantly decreased Tau and inhibited its phosphorylation in the hippocampus of OXYS and Wistar rats. Importantly, rapamycin treatment caused a compensatory increase in levels of S6 and correspondingly levels of phospo-S6 in the frontal cortex, indicating that some downstream events were compensatory preserved, explaining the lack of toxicity. We conclude that rapamycin in low chronic doses can suppress brain aging.

Show MeSH
Related in: MedlinePlus