APOE-mediated lipid transport prevents C1q-related synaptic loss after spinal cord injury via attenuating macrophage lipid stress.

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of Apoe disrupts this intercellular lipid transport, culminating in pathological lipid retention that activates the Hippo signalling cascade and transcriptionally induces complement component C1q. This excess C1q aberrantly tags intact synapses for excessive microglial pruning, leading to significant synaptic loss and impaired locomotor function recovery. Direct blockade of C1q using neutralizing antibodies recapitulated these neuroprotective effects, confirming C1q as the critical mediator. Crucially, macrophage-specific APOE re-expression reverses this entire cascade, preserving synapses and restoring locomotor function (BMS score: 4.81 ± 0.21 (Apoe) vs. 1.75 ± 1.28 (NC); Incline plane: 69.24° ± 2.33° (Apoe) vs. 51.66° ± 5.14° (NC) in Apoe−/− mice). These findings identify the APOE-Hippo-C1q pathway in macrophages as a novel therapeutic target for SCI.