Xu Yuan, Shao Naiyuan, Zhi Feng, Chen Ronghua, Yang Yilin, Li Jiahui, Xia Ying, Peng Ya
Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu, China.
Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China.
Alzheimers Res Ther. 2025 Feb 1;17(1):35. doi: 10.1186/s13195-025-01682-1.
Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer's disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies.
We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data.
We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway.
These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses.
近期研究表明，阿片受体信号传导可能对阿尔茨海默病（AD）的病理变化及相关行为功能障碍产生不同影响。然而，阿片受体亚型在AD病理中的具体作用和机制仍不明确，存在重大争议。
我们使用转基因APP/PS1小鼠模型和BV2细胞系，在行为、分子和细胞水平上比较了δ-阿片受体（DOR）和μ-阿片受体（MOR）介导的对AD相关认知缺陷、病理变化、神经炎症、细胞死亡的影响。采用非配对t检验和单因素/双因素方差分析（ANOVA）来分析数据的统计学意义。
我们在APP/PS1小鼠模型中显示了DOR的独特作用及其与MOR在AD损伤中的主要差异。UFP-512激活DOR可减轻认知障碍、减少β-淀粉样蛋白（Aβ）的产生和聚集，并保护APP/PS1小鼠的神经元免于凋亡，而DAMGO激活MOR则无此作用。DOR和MOR还对APP/PS1小鼠和体外AD细胞模型中的小胶质细胞产生不同调节作用，DOR介导抑制AD病理中小胶质细胞的过度激活和促炎细胞因子的释放。基因表达谱进一步揭示，DOR/MOR的变化与AD中小胶质细胞的稳态特征和高迁移率族蛋白B1（HMGB1）密切相关。DOR激活抑制HMGB1的分泌及其从细胞核到细胞质的转位。我们的体外研究进一步证实，DOR过表达可减轻小胶质细胞的炎症反应，并通过HMGB1-NF-κB信号通路使神经元免受AD损伤。
这些新发现揭示了DOR通过调节与小胶质细胞相关的炎症反应在神经保护免受AD损伤方面以前未被认识的作用。
