GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease
Abstract Background G protein-coupled receptor 43 (GPR43) is a critical signaling molecule involved in maintaining energy balance and immune homeostasis, making it a widely studied drug target. However, its role in Alzheimer’s disease (AD) remains unclear. This study aims to investigate the effects...
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BMC
2025-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01269-4 |
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| author | Xiaoqin Wang Shijing Wu Zhangjing Deng Mengyu Yan Dandan Wang Maojun Yang Fuxing Zhong Jiaqi Song Lihua Chen Yingxi Chen Qi Tian Weihua Yu Yang Lü |
| author_facet | Xiaoqin Wang Shijing Wu Zhangjing Deng Mengyu Yan Dandan Wang Maojun Yang Fuxing Zhong Jiaqi Song Lihua Chen Yingxi Chen Qi Tian Weihua Yu Yang Lü |
| author_sort | Xiaoqin Wang |
| collection | DOAJ |
| description | Abstract Background G protein-coupled receptor 43 (GPR43) is a critical signaling molecule involved in maintaining energy balance and immune homeostasis, making it a widely studied drug target. However, its role in Alzheimer’s disease (AD) remains unclear. This study aims to investigate the effects of GPR43 activation in an Aβ1−42-induced AD mouse model and to elucidate the underlying mechanisms. Methods Experiments were performed using Aβ1-42-induced C57BL/6 mice (in vivo model) and the mouse hippocampal neuronal cell line HT22 (in vitro model). GPR43 gene expression and protein levels were analyzed in the brains of AD mice. Lentivirus-mediated GPR43 overexpression was employed to assess its effects on AD-like behaviors and pathological features. Cyclosporin A (CSA), a cyclophilin D (CypD) inhibitor, was used to investigate the pathological mechanisms of GPR43 in AD. Result Compared to wild-type mice, GPR43 expression was downregulated in the cerebral cortex and hippocampus of Aβ1-42-induced AD mice and was primarily localized to neurons. GPR43 activation improved spatial learning and memory in AD mice. Furthermore, it upregulated the expression of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and synaptophysin (SYP), indicating enhanced neuronal and synaptic function. GPR43 upregulation also modulated the levels of mitochondrial damage-related enzymes, including superoxide dismutase (SOD), malondialdehyde (MDA), and lactate dehydrogenase (LDH) levels, and reduced mitochondrial swelling. Notably, GPR43 downregulated CypD protein levels, which are linked to mitochondrial permeability transition pore (mPTP) channels, thereby inhibiting apoptosis. Finally, in GPR43-knockdown cells, treatment with CSA significantly reduced the apoptosis rate, decreased BAX and Caspase-9 levels, and increased BCL-2 expression. Conclusion GPR43 inhibits apoptosis in AD mice through the CypD signaling pathway, highlighting its potential as a novel target for drug development in AD treatment. |
| format | Article |
| id | doaj-art-5cf54d5efacf466997ccbca120f94051 |
| institution | OA Journals |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-5cf54d5efacf466997ccbca120f940512025-08-20T02:30:42ZengBMCMolecular Medicine1528-36582025-06-0131112010.1186/s10020-025-01269-4GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s diseaseXiaoqin Wang0Shijing Wu1Zhangjing Deng2Mengyu Yan3Dandan Wang4Maojun Yang5Fuxing Zhong6Jiaqi Song7Lihua Chen8Yingxi Chen9Qi Tian10Weihua Yu11Yang Lü12Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityInstitutes of Neuroscience, Chongqing Medical UniversityThe First People’s Hospital of Shuangliu DistrictThe First People’s Hospital of Shuangliu DistrictDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityInstitutes of Neuroscience, Chongqing Medical UniversityDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityInstitutes of Neuroscience, Chongqing Medical UniversityDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityInstitutes of Neuroscience, Chongqing Medical UniversityDepartment of Geriatrics, The First Affiliated Hospital of Chongqing Medical UniversityAbstract Background G protein-coupled receptor 43 (GPR43) is a critical signaling molecule involved in maintaining energy balance and immune homeostasis, making it a widely studied drug target. However, its role in Alzheimer’s disease (AD) remains unclear. This study aims to investigate the effects of GPR43 activation in an Aβ1−42-induced AD mouse model and to elucidate the underlying mechanisms. Methods Experiments were performed using Aβ1-42-induced C57BL/6 mice (in vivo model) and the mouse hippocampal neuronal cell line HT22 (in vitro model). GPR43 gene expression and protein levels were analyzed in the brains of AD mice. Lentivirus-mediated GPR43 overexpression was employed to assess its effects on AD-like behaviors and pathological features. Cyclosporin A (CSA), a cyclophilin D (CypD) inhibitor, was used to investigate the pathological mechanisms of GPR43 in AD. Result Compared to wild-type mice, GPR43 expression was downregulated in the cerebral cortex and hippocampus of Aβ1-42-induced AD mice and was primarily localized to neurons. GPR43 activation improved spatial learning and memory in AD mice. Furthermore, it upregulated the expression of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95), and synaptophysin (SYP), indicating enhanced neuronal and synaptic function. GPR43 upregulation also modulated the levels of mitochondrial damage-related enzymes, including superoxide dismutase (SOD), malondialdehyde (MDA), and lactate dehydrogenase (LDH) levels, and reduced mitochondrial swelling. Notably, GPR43 downregulated CypD protein levels, which are linked to mitochondrial permeability transition pore (mPTP) channels, thereby inhibiting apoptosis. Finally, in GPR43-knockdown cells, treatment with CSA significantly reduced the apoptosis rate, decreased BAX and Caspase-9 levels, and increased BCL-2 expression. Conclusion GPR43 inhibits apoptosis in AD mice through the CypD signaling pathway, highlighting its potential as a novel target for drug development in AD treatment.https://doi.org/10.1186/s10020-025-01269-4Alzheimer’s diseaseG protein-coupled receptor 43Cyclophilin DNeuronsSynapsesMitochondria |
| spellingShingle | Xiaoqin Wang Shijing Wu Zhangjing Deng Mengyu Yan Dandan Wang Maojun Yang Fuxing Zhong Jiaqi Song Lihua Chen Yingxi Chen Qi Tian Weihua Yu Yang Lü GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease Molecular Medicine Alzheimer’s disease G protein-coupled receptor 43 Cyclophilin D Neurons Synapses Mitochondria |
| title | GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease |
| title_full | GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease |
| title_fullStr | GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease |
| title_full_unstemmed | GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease |
| title_short | GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease |
| title_sort | gpr43 regulates mitochondrial apoptosis through the cyclophilin d pathway in alzheimer s disease |
| topic | Alzheimer’s disease G protein-coupled receptor 43 Cyclophilin D Neurons Synapses Mitochondria |
| url | https://doi.org/10.1186/s10020-025-01269-4 |
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