Publication
Changes in transcription factors related to mitochondrial biogenesis and antioxidant defense in alzheimer’s disease models
| Summary: | Alzheimer's disease (AD) is the major cause of dementia in the elderly population. Abnormal accumulation of amyloid beta peptide (Aβ) in the brain is one of the hallmarks of the disease and oxidative stress and mitochondrial and synaptic dysfunction have also been observed in AD. In addition, several transcription factors that regulate the transcription of genes encoding proteins involved in antioxidant defenses and mitochondrial biogenesis are also altered in AD, pointing out to a possible role of (Aβ) in the regulation of the transcription of some genes. In this work, we evaluated the alterations in the nuclear levels of transcription factors related to mitochondrial biogenesis (PGC-1α and Tfam), antioxidant defense (Nrfβ and PGC-1α) and Nmethyl- D-aspartate receptor (NMDAR)-linked cAMP signaling (CREB) and some of their target proteins (SOD1, GLCc and Tfam) in mature rat cortical cells (15 DIV) exposed to Aβ1-42 oligomer-enriched population and also in the cortex of 3 and >15 month-old (mo) 3xTg-AD mice. We also evaluated the relationship between the changes in transcription factors and ROS production, as well as the role of NMDAR in Aβ1-42-mediated effects. Our data showed increased nuclear PGC-1α levels in γ and 15 mo γxTg-AD mice and in cortical cells exposed to Aβ1-42 for 2 h. The latter decreased to values similar to the control in the presence of ifenprodil and memantine, suggesting an important role for GluN2B subunits in Aβ1-42-mediated rise in PGC-1α levels. Nuclear Nrfβ protein levels were reduced in 15 mo 3xTg-AD male mice cortices; nevertheless, decreased SOD1 levels was observed in 3 mo 3xTg- AD and in both 15 mo WT and 3xTg-AD mice. Nrf2 protein and phosphorylation levels also decreased in cortical cells exposed to Aβ1-42 for 24 h, which correlated with enhanced ROS production. NMDAR antagonists did not prevent the effects of Aβ1-42 on the nuclear levels of pNrfβ and Nrfβ, suggesting that Aβ-mediated effects may implicate other receptor(s) or a direct impairment by Aβ1-42 in the phosphorylation of Nrf2 at Ser 40, thus preventing Nrf2 translocation to the nucleus.Similarly to Nrfβ, nuclear CREB protein levels were reduced in cortical cells exposed to Aβ1-42 for 24 h and in the cortex of 15 mo 3xTg-AD mice. In contrast, nuclear pCREB levels were increased in cortical cells exposed to Aβ1-42 for β4 h. A-mediated effects in CREBwere largely prevented by memantine, a selective NMDAR antagonists used in the treatment of moderatesevere cases of AD. In conclusion, PGC-1α levels are enhanced in early phases of A exposure, whereas CREB and Nrf2 decrease in later phases. Reduced Nrf2 may contribute for increased production of ROS and consequently to the worsening of cognitive deficits. |
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| Main Authors: | Caldeira, Gladys Tarcila Lima |
| Subject: | Nrf2 PGC-1α CREB Stresse oxidativo Biogénese mitocondrial Receptores NMDA Péptido beta-amilóide ROS |
| Year: | 2012 |
| Country: | Portugal |
| Document type: | master thesis |
| Access type: | open access |
| Associated institution: | Universidade de Coimbra |
| Language: | English |
| Origin: | Estudo Geral - Universidade de Coimbra |
| Summary: | Alzheimer's disease (AD) is the major cause of dementia in the elderly population. Abnormal accumulation of amyloid beta peptide (Aβ) in the brain is one of the hallmarks of the disease and oxidative stress and mitochondrial and synaptic dysfunction have also been observed in AD. In addition, several transcription factors that regulate the transcription of genes encoding proteins involved in antioxidant defenses and mitochondrial biogenesis are also altered in AD, pointing out to a possible role of (Aβ) in the regulation of the transcription of some genes. In this work, we evaluated the alterations in the nuclear levels of transcription factors related to mitochondrial biogenesis (PGC-1α and Tfam), antioxidant defense (Nrfβ and PGC-1α) and Nmethyl- D-aspartate receptor (NMDAR)-linked cAMP signaling (CREB) and some of their target proteins (SOD1, GLCc and Tfam) in mature rat cortical cells (15 DIV) exposed to Aβ1-42 oligomer-enriched population and also in the cortex of 3 and >15 month-old (mo) 3xTg-AD mice. We also evaluated the relationship between the changes in transcription factors and ROS production, as well as the role of NMDAR in Aβ1-42-mediated effects. Our data showed increased nuclear PGC-1α levels in γ and 15 mo γxTg-AD mice and in cortical cells exposed to Aβ1-42 for 2 h. The latter decreased to values similar to the control in the presence of ifenprodil and memantine, suggesting an important role for GluN2B subunits in Aβ1-42-mediated rise in PGC-1α levels. Nuclear Nrfβ protein levels were reduced in 15 mo 3xTg-AD male mice cortices; nevertheless, decreased SOD1 levels was observed in 3 mo 3xTg- AD and in both 15 mo WT and 3xTg-AD mice. Nrf2 protein and phosphorylation levels also decreased in cortical cells exposed to Aβ1-42 for 24 h, which correlated with enhanced ROS production. NMDAR antagonists did not prevent the effects of Aβ1-42 on the nuclear levels of pNrfβ and Nrfβ, suggesting that Aβ-mediated effects may implicate other receptor(s) or a direct impairment by Aβ1-42 in the phosphorylation of Nrf2 at Ser 40, thus preventing Nrf2 translocation to the nucleus.Similarly to Nrfβ, nuclear CREB protein levels were reduced in cortical cells exposed to Aβ1-42 for 24 h and in the cortex of 15 mo 3xTg-AD mice. In contrast, nuclear pCREB levels were increased in cortical cells exposed to Aβ1-42 for β4 h. A-mediated effects in CREBwere largely prevented by memantine, a selective NMDAR antagonists used in the treatment of moderatesevere cases of AD. In conclusion, PGC-1α levels are enhanced in early phases of A exposure, whereas CREB and Nrf2 decrease in later phases. Reduced Nrf2 may contribute for increased production of ROS and consequently to the worsening of cognitive deficits. |
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