Targeting the complement-mTOR-autophagy axis: the role of apolipoprotein E in depression

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.