Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Branch of National Clinical Research Center for Metabolic Diseases, Wuhan, Hubei, China.
J Neuroinflammation. 2024 Aug 2;21(1):192. doi: 10.1186/s12974-024-03183-8.
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.
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.
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.
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.
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 中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尚不清楚。在这里，我们通过其在中枢神经系统中与配对免疫球蛋白样受体 B（PirB）的相互作用，探索了 ANGPTL8 在糖尿病相关认知功能障碍中的作用。
测量了伴有认知功能障碍的 2 型糖尿病患者和对照组个体的 ANGPTL8 水平。构建了糖尿病相关认知功能障碍的小鼠模型，以研究 ANGPTL8 在认知功能中的作用。通过 Barnes 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、突触和轴突标志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，并观察后续变化。此外，还验证了阻断 PirB 及其下游途径后 ANGPTL8 引起的变化。最后，生成了中枢神经系统特异性敲除 Angptl8 和 PirB 小鼠，并进行了相关的体内实验。
在这里，我们证明了在糖尿病大脑中，ANGPTL8 由神经元分泌到海马体，导致神经炎症和突触可塑性受损。此外，神经元特异性 Angptl8 敲除可预防糖尿病相关认知功能障碍和神经炎症。机制上，ANGPTL8 通过其受体 PirB 与神经元和小胶质细胞平行作用，表现为神经元中突触和轴突标志物的下调以及小胶质细胞中促炎细胞因子表达的上调。在体内，PirB 小鼠表现出对 ANGPTL8 诱导的神经炎症和突触损伤的抗性。
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，并确定了 ANGPTL8-PirB 信号通路作为该疾病治疗的潜在靶点。
