Zhang Jiawei, Zhang Yaxuan, Liu Lan, Zhang Mengyuan, Zhang Xiaojie, Deng Jiangshan, Zhao Fei, Lin Qing, Zheng Xue, Fu Bing, Zhao Yuwu, Wang Xiuzhe
Department of Neurology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Yishan Road 600, Shanghai, 200233, China.
Department of Neurology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
J Neuroinflammation. 2025 Jan 8;22(1):5. doi: 10.1186/s12974-024-03325-y.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide, and microglia are thought to play a central role in neuroinflammatory events occurring in AD. Chemerin, an adipokine, has been implicated in inflammatory diseases and central nervous system disorders, yet its precise function on microglial response in AD remains unknown.
The APP/PS1 mice were treated with different dosages of chemerin-9 (30 and 60 µg/kg), a bioactive nonapeptide derived from chemerin, every other day for 8 weeks consecutively. The primary mouse microglia were stimulated by amyloid beta 42 (Aβ) oligomers followed by treatment with chemerin-9 in vitro. ChemR23 inhibitor α-NETA was further used to investigate whether the effects of chemerin-9 were ChemR23-dependent.
We found that the expression of chemerin and ChemR23 was increased in AD. Intriguingly, treatment with chemerin-9 significantly ameliorated Aβ deposition and cognitive impairment of the APP/PS1 mice, with decreased microglial proinflammatory activity and increased phagocytic activity. Similarly, chemerin-9-treated primary microglia showed increased phagocytic ability and decreased NLRP3 inflammasome activation. However, the ChemR23 inhibitor α-NETA abolished the neuroprotective microglial response of chemerin-9.
Collectively, our data demonstrate that chemerin-9 ameliorates cognitive deficits in APP/PS1 transgenic mice by boosting a neuroprotective microglial phenotype.
阿尔茨海默病（AD）是一种在全球普遍存在的神经退行性疾病，小胶质细胞被认为在AD发生的神经炎症事件中起核心作用。chemerin是一种脂肪因子，与炎症性疾病和中枢神经系统疾病有关，但其在AD中对小胶质细胞反应的确切功能仍不清楚。
对APP/PS1小鼠每隔一天连续8周给予不同剂量的chemerin-9（30和60μg/kg），chemerin-9是一种从chemerin衍生而来的具有生物活性的九肽。原代小鼠小胶质细胞先用淀粉样β蛋白42（Aβ）寡聚体刺激，然后在体外给予chemerin-9处理。进一步使用ChemR23抑制剂α-NETA来研究chemerin-9的作用是否依赖于ChemR23。
我们发现AD中chemerin和ChemR23的表达增加。有趣的是，用chemerin-9治疗可显著改善APP/PS1小鼠的Aβ沉积和认知障碍，同时小胶质细胞的促炎活性降低，吞噬活性增加。同样，用chemerin-9处理的原代小胶质细胞显示吞噬能力增强，NLRP3炎性小体激活减少。然而，ChemR23抑制剂α-NETA消除了chemerin-9对小胶质细胞的神经保护反应。
总体而言，我们的数据表明chemerin-9通过增强小胶质细胞的神经保护表型来改善APP/PS1转基因小鼠的认知缺陷。
