抑制 ANGPTL8 可通过 PirB 信号通路减少突触损失，从而预防与糖尿病相关的认知功能障碍。

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2024-08-02 DOI:10.1186/s12974-024-03183-8

Xiaoyu Meng, Danpei Li, Ranran Kan, Yuxi Xiang, Limeng Pan, Yaming Guo, Peng Yu, Peiqiong Luo, Huajie Zou, Li Huang, Yurong Zhu, Beibei Mao, Yi He, Lei Xie, Jialu Xu, Xiaoyan Liu, Wenjun Li, Yong Chen, Suiqiang Zhu, Yan Yang, Xuefeng Yu

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引用次数: 0

摘要

背景：2型糖尿病（T2D）与认知功能障碍的风险增加有关。血管生成素样蛋白8（ANGPTL8）是T2D的一个重要调节因子，但ANGPTL8在糖尿病相关认知功能障碍中的作用仍然未知。在此，我们通过ANGPTL8与中枢神经系统中成对免疫球蛋白样受体B（PirB）的相互作用，探讨了ANGPTL8在糖尿病相关认知功能障碍中的作用：方法：测定认知功能障碍的2型糖尿病患者和对照组个体的ANGPTL8水平。为了研究 ANGPTL8 在认知功能中的作用，构建了糖尿病相关认知功能障碍的小鼠模型。通过巴恩斯迷宫测试和新物体识别测试评估小鼠的认知功能，并测量 ANGPTL8、突触和轴突标记物以及促炎细胞因子的水平。用重组 ANGPTL8 蛋白（rA8）处理原代神经元和小胶质细胞，并检测随后的变化。此外，在阻断 PirB 及其下游通路后，ANGPTL8 诱导的变化也得到了验证。最后，生成了中枢神经系统特异性敲除 Angptl8 的小鼠和 PirB-/- 小鼠，并进行了相关的体内实验：结果：我们在此证实，在糖尿病脑中，ANGPTL8由神经元分泌到海马，导致神经炎症和突触可塑性受损。此外，神经元特异性ANGPTL8基因敲除可预防糖尿病相关的认知功能障碍和神经炎症。从机理上讲，ANGPTL8通过其受体PirB平行作用于神经元和小胶质细胞，表现为神经元突触和轴突标志物的下调和小胶质细胞促炎细胞因子表达的上调。在体内，PirB-/-小鼠对ANGPTL8诱导的神经炎症和突触损伤表现出抵抗力：综上所述，我们的研究结果揭示了 ANGPTL8 在糖尿病相关认知功能障碍发病机制中的作用，并确定 ANGPTL8-PirB 信号通路是治疗这种疾病的潜在靶点。

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Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

Background: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system.

Methods: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB^-/- mice were generated, and relevant in vivo experiments were performed.

Results: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB^-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage.

Conclusion: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

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来源期刊

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.