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Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.

Bai X, Wey MC, Fernandez E, Hart MJ, Gelfond J, Bokov AF, Rani S, Strong R - Pathobiol Aging Age Relat Dis (2015)

Bottom Line: Rapamycin did not alter A53T α-synuclein content.Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice.Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT

Background: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy.

Methods: We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches.

Results: After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.

Conclusion: Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.

No MeSH data available.


Related in: MedlinePlus

Effect of RAPA on 4-HNE protein adducts in midbrain, striatum, brain stem, cerebellum, and spinal cord. Age-matched female WT and TG mice were fed mouse diet incorporated with microencapsulated RAPA or the microencapsulation material Eudragit S100 (Control) from 13 weeks of age for 24 weeks. Each well of a 4–12% Criterion gel was loaded with 40 µg brain tissue lysate. Immunoreactive bands were quantified by Odyssey software. Data represent the mean±SEM. Two-way ANOVAs followed by post hoc Bonferonni tests were used to analyze effects of genotype and RAPA on levels of synaptophysin in either sex. *p<0.05, WT control versus WT RAPA; **p<0.05, WT control versus TG control; ***p<0.05, TG control versus TG RAPA.
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Figure 0002: Effect of RAPA on 4-HNE protein adducts in midbrain, striatum, brain stem, cerebellum, and spinal cord. Age-matched female WT and TG mice were fed mouse diet incorporated with microencapsulated RAPA or the microencapsulation material Eudragit S100 (Control) from 13 weeks of age for 24 weeks. Each well of a 4–12% Criterion gel was loaded with 40 µg brain tissue lysate. Immunoreactive bands were quantified by Odyssey software. Data represent the mean±SEM. Two-way ANOVAs followed by post hoc Bonferonni tests were used to analyze effects of genotype and RAPA on levels of synaptophysin in either sex. *p<0.05, WT control versus WT RAPA; **p<0.05, WT control versus TG control; ***p<0.05, TG control versus TG RAPA.

Mentions: The level of 4-HNE-adducted proteins (Fig. 2, Supplementary Fig. 4) was significantly increased in the cerebellum, midbrain, and striatum of male TG compared to WT (p<0.05). RAPA treatment was associated with significant (p<0.05) decreases in 4-HNE-protein adducts in each of the five brain regions tested from both WT and TG female. There were significant (p<0.05) decreases in 4-HNE-protein adducts in four of the five brain regions from RAPA-treated male WT. There was also a trend toward decreases in the mean content of 4-HNE-protein adducts in each of the five brain regions in RAPA-treated male TG, achieving significance (p<0.05) in the midbrain.


Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy.

Bai X, Wey MC, Fernandez E, Hart MJ, Gelfond J, Bokov AF, Rani S, Strong R - Pathobiol Aging Age Relat Dis (2015)

Effect of RAPA on 4-HNE protein adducts in midbrain, striatum, brain stem, cerebellum, and spinal cord. Age-matched female WT and TG mice were fed mouse diet incorporated with microencapsulated RAPA or the microencapsulation material Eudragit S100 (Control) from 13 weeks of age for 24 weeks. Each well of a 4–12% Criterion gel was loaded with 40 µg brain tissue lysate. Immunoreactive bands were quantified by Odyssey software. Data represent the mean±SEM. Two-way ANOVAs followed by post hoc Bonferonni tests were used to analyze effects of genotype and RAPA on levels of synaptophysin in either sex. *p<0.05, WT control versus WT RAPA; **p<0.05, WT control versus TG control; ***p<0.05, TG control versus TG RAPA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549373&req=5

Figure 0002: Effect of RAPA on 4-HNE protein adducts in midbrain, striatum, brain stem, cerebellum, and spinal cord. Age-matched female WT and TG mice were fed mouse diet incorporated with microencapsulated RAPA or the microencapsulation material Eudragit S100 (Control) from 13 weeks of age for 24 weeks. Each well of a 4–12% Criterion gel was loaded with 40 µg brain tissue lysate. Immunoreactive bands were quantified by Odyssey software. Data represent the mean±SEM. Two-way ANOVAs followed by post hoc Bonferonni tests were used to analyze effects of genotype and RAPA on levels of synaptophysin in either sex. *p<0.05, WT control versus WT RAPA; **p<0.05, WT control versus TG control; ***p<0.05, TG control versus TG RAPA.
Mentions: The level of 4-HNE-adducted proteins (Fig. 2, Supplementary Fig. 4) was significantly increased in the cerebellum, midbrain, and striatum of male TG compared to WT (p<0.05). RAPA treatment was associated with significant (p<0.05) decreases in 4-HNE-protein adducts in each of the five brain regions tested from both WT and TG female. There were significant (p<0.05) decreases in 4-HNE-protein adducts in four of the five brain regions from RAPA-treated male WT. There was also a trend toward decreases in the mean content of 4-HNE-protein adducts in each of the five brain regions in RAPA-treated male TG, achieving significance (p<0.05) in the midbrain.

Bottom Line: Rapamycin did not alter A53T α-synuclein content.Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice.Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

ABSTRACT

Background: Synucleinopathy is any of a group of age-related neurodegenerative disorders including Parkinson's disease, multiple system atrophy, and dementia with Lewy Bodies, which is characterized by α-synuclein inclusions and parkinsonian motor deficits affecting millions of patients worldwide. But there is no cure at present for synucleinopathy. Rapamycin has been shown to be neuroprotective in several in vitro and in vivo synucleinopathy models. However, there are no reports on the long-term effects of RAPA on motor function or measures of neurodegeneration in models of synucleinopathy.

Methods: We determined whether long-term feeding a rapamycin diet (14 ppm in diet; 2.25 mg/kg body weight/day) improves motor function in neuronal A53T α-synuclein transgenic mice (TG) and explored underlying mechanisms using a variety of behavioral and biochemical approaches.

Results: After 24 weeks of treatment, rapamycin improved performance on the forepaw stepping adjustment test, accelerating rotarod and pole test. Rapamycin did not alter A53T α-synuclein content. There was no effect of rapamycin treatment on midbrain or striatal monoamines or their metabolites. Proteins adducted to the lipid peroxidation product 4-hydroxynonenal were decreased in brain regions of both wild-type and TG mice treated with rapamycin. Reduced levels of the presynaptic marker synaptophysin were found in several brain regions of TG mice. Rapamycin attenuated the loss of synaptophysin protein in the affected brain regions. Rapamycin also attenuated the loss of synaptophysin protein and prevented the decrease of neurite length in SH-SY5Y cells treated with 4-hydroxynonenal.

Conclusion: Taken together, these data suggest that rapamycin, an FDA approved drug, may prove useful in the treatment of synucleinopathy.

No MeSH data available.


Related in: MedlinePlus