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

作者：Xiaoqin Wang, Shijing Wu, Zhangjing Deng, Mengyu Yan, Dandan Wang, Maojun Yang, Fuxing Zhong, Jiaqi Song, Lihua Chen, Yingxi Chen, Qi Tian, Weihua Yu, Lu Yang · 发表于：Molecular Medicine · 年份：2025 · DOI：10.1186/s10020-025-01269-4 · 被引用次数：4 · 研究领域：Receptor Mechanisms and Signaling、Pancreatic function and diabetes、Signaling Pathways in Disease

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)...