Table_2_The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice.xlsx

Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

脊髓损伤（SCI）是一类毁灭性神经创伤。携带1个或2个载脂蛋白E（ApoE）4等位基因的患者，在脊髓损伤后功能预后更差且住院时间更长，但该遗传关联的细胞与分子基础仍不甚明确。因此，亟需构建可精准复刻脊髓损伤后预后相关遗传决定因素的动物模型，以推动改善机体功能的治疗手段研发。本研究针对表达人源ApoE3或ApoE4的转基因小鼠，开展中度挫伤型脊髓损伤模型的预后分析。结果显示，脊髓损伤后ApoE4小鼠的运动功能与协调能力更差。组织学检测发现，脊髓损伤后ApoE4小鼠的胶质细胞染色更强，同时伴随神经元出芽标志物水平降低。批量RNA测序（bulk RNA sequencing）结果表明，脊髓损伤后7天，ApoE4小鼠体内上调基因中，亚细胞过程（subcellular processes, SCPs）如细胞外基质组织与炎症反应相关通路显著富集。与之相反，脊髓损伤后21天，ApoE3小鼠体内与神经元动作电位、神经元投射发育相关的亚细胞过程显著上调。综上，本研究构建了与临床相关的脊髓损伤小鼠模型，可复刻携带上述等位基因的个体中ApoE基因型对脊髓损伤后功能的影响，并揭示ApoE4小鼠恢复较差的潜在机制为胶质细胞活化、神经元出芽与突触活性丧失。