Li Yong, Xu Chengyuan, Liu Jing, Guo Mengru, Wang Jia, Bai Xianbing, Cheng Yujie, Luan Xinyue, Pei Huailong, Zhang Chenlei, Liu Huan, Chen Ming, Tang Binliang
Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China.
BMC Biol. 2025 Jul 28;23(1):228. doi: 10.1186/s12915-025-02301-z.
Depression is a highly prevalent and debilitating psychiatric disorder, and while Apolipoprotein E (ApoE), a critical regulator of lipid transport and neuronal function, has been implicated in regulating depressive behaviors, the underlying mechanisms remain insufficiently understood.
In this study, we explored the role of ApoE in depression using complementary animal models. We observed significantly reduced ApoE levels in the hippocampus of both chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-induced depression models, with ApoE knockout (ApoE) mice exhibiting exacerbated depressive-like behaviors. Hippocampal ApoE overexpression effectively reversed these behavioral deficits, demonstrating ApoE's essential role in modulating depressive-like behaviors. Mechanistically, ApoE knockout triggered microglial hyperactivation and complement C3 elevation, leading to sustained mTOR pathway activation and subsequent impairment of autophagy. The critical role of this pathway was validated through pharmacological intervention, where treatment with the mTOR inhibitor rapamycin restored autophagy, reduced neuroinflammation, and alleviated depressive behaviors.
These findings demonstrate that ApoE regulates depressive behaviors by modulating the complement-mTOR-autophagy axis, identifying multiple potential therapeutic targets for clinical intervention in depression.
抑郁症是一种高度流行且使人衰弱的精神疾病，虽然载脂蛋白E（ApoE）作为脂质转运和神经元功能的关键调节因子，已被证实参与调节抑郁行为，但其潜在机制仍未得到充分理解。
在本研究中，我们使用互补的动物模型探究了ApoE在抑郁症中的作用。我们观察到，在慢性社会挫败应激（CSDS）和脂多糖（LPS）诱导的抑郁症模型中，海马体中的ApoE水平均显著降低，而ApoE基因敲除（ApoE）小鼠表现出加剧的抑郁样行为。海马体中ApoE的过表达有效逆转了这些行为缺陷，证明了ApoE在调节抑郁样行为中的重要作用。从机制上讲，ApoE基因敲除引发了小胶质细胞的过度激活和补体C3的升高，导致mTOR通路持续激活以及随后的自噬受损。通过药物干预验证了该通路的关键作用，使用mTOR抑制剂雷帕霉素进行治疗可恢复自噬、减轻神经炎症并缓解抑郁行为。
这些发现表明，ApoE通过调节补体 - mTOR - 自噬轴来调节抑郁行为，为抑郁症的临床干预确定了多个潜在的治疗靶点。
