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Background <p>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 Aβ<sub>1−42</sub>-induced AD mouse model and to elucidate the underlying mechanisms.</p> Methods <p>Experiments were performed using Aβ<sub>1-42</sub>-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.</p> Result <p>Compared to wild-type mice, GPR43 expression was downregulated in the cerebral cortex and hippocampus of Aβ<sub>1-42</sub>-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.</p> Conclusion <p>GPR43 inhibits apoptosis in AD mice through the CypD signaling pathway, highlighting its potential as a novel target for drug development in AD treatment.</p>

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GPR43 regulates mitochondrial apoptosis through the cyclophilin D pathway in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • 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

摘要

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.