Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments
In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related dec...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/15197 |
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| author | Artem P. Gureev Victoria G. Khorolskaya Irina S. Sadovnikova Ekaterina A. Shaforostova Vadim R. Cherednichenko Inna Y. Burakova Egor Y. Plotnikov Vasily N. Popov |
| author_facet | Artem P. Gureev Victoria G. Khorolskaya Irina S. Sadovnikova Ekaterina A. Shaforostova Vadim R. Cherednichenko Inna Y. Burakova Egor Y. Plotnikov Vasily N. Popov |
| author_sort | Artem P. Gureev |
| collection | DOAJ |
| description | In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the <i>Nfe2l2</i> expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the <i>Bdnf</i> expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in <i>Bdnf</i> expression in the hippocampus, <i>Nfe2l2</i> expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment. |
| first_indexed | 2024-03-09T17:44:19Z |
| format | Article |
| id | doaj.art-3106f8a5f23e445ca410c1fbe5f2b1bc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:44:19Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3106f8a5f23e445ca410c1fbe5f2b1bc2023-11-24T11:14:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123231519710.3390/ijms232315197Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive ImpairmentsArtem P. Gureev0Victoria G. Khorolskaya1Irina S. Sadovnikova2Ekaterina A. Shaforostova3Vadim R. Cherednichenko4Inna Y. Burakova5Egor Y. Plotnikov6Vasily N. Popov7Department of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaA.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, RussiaDepartment of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, RussiaIn this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the <i>Nfe2l2</i> expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the <i>Bdnf</i> expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in <i>Bdnf</i> expression in the hippocampus, <i>Nfe2l2</i> expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment.https://www.mdpi.com/1422-0067/23/23/15197agingcognitive deficitnuclear erythroid 2-related factor 2mammalian target of rapamycin complex 1brain-derived neurotrophic factormitochondrial DNA damage |
| spellingShingle | Artem P. Gureev Victoria G. Khorolskaya Irina S. Sadovnikova Ekaterina A. Shaforostova Vadim R. Cherednichenko Inna Y. Burakova Egor Y. Plotnikov Vasily N. Popov Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments International Journal of Molecular Sciences aging cognitive deficit nuclear erythroid 2-related factor 2 mammalian target of rapamycin complex 1 brain-derived neurotrophic factor mitochondrial DNA damage |
| title | Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments |
| title_full | Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments |
| title_fullStr | Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments |
| title_full_unstemmed | Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments |
| title_short | Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments |
| title_sort | age related decline in nrf2 are signaling is associated with the mitochondrial dna damage and cognitive impairments |
| topic | aging cognitive deficit nuclear erythroid 2-related factor 2 mammalian target of rapamycin complex 1 brain-derived neurotrophic factor mitochondrial DNA damage |
| url | https://www.mdpi.com/1422-0067/23/23/15197 |
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