Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two ApoE4 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.

中文翻译：

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人ApoE4变体降低雄性小鼠脊髓不完全损伤后的功能恢复和神经元发芽

脊髓损伤（SCI）是神经创伤的毁灭性形式。携带一个或两个ApoE4等位基因的患者在SCI后表现出较差的功能结局和更长的住院时间，但是对于这种遗传联系的细胞和分子基础仍然知之甚少。因此，非常需要生成动物模型以准确复制SCI后结果的遗传决定因素，以刺激开发改善身体机能的治疗方法。在这里，我们检查了中度挫伤后表达人ApoE3或ApoE4的转基因小鼠的结局。Spo后，ApoE4小鼠的运动功能和协调能力变差。组织学检查显示，SCI后ApoE4小鼠的神经胶质染色更大，与神经元发芽标记物水平降低有关。大量RNA测序表明，亚细胞过程（SCP）在Spo后7天，ApoE4变体中的上调基因在细胞外基质组织和炎症反应等方面的排名较高。相反，与ApoE3小鼠的神经元动作电位和神经元投射发育有关的SCP在21天时增加。总而言之，我们的结果揭示了一个临床相关的SCI小鼠模型，该模型概括了ApoE基因型对携带这些等位基因的个体SCI后功能的影响，并表明ApoE4动物恢复较差的潜在机制涉及神经胶质激活以及发芽和突触丧失活动。与神经元动作电位和神经元投射发育有关的SCP在21天时增加。总而言之，我们的结果揭示了一个临床相关的SCI小鼠模型，该模型概括了ApoE基因型对携带这些等位基因的个体SCI后功能的影响，并表明ApoE4动物恢复较差的潜在机制涉及神经胶质激活以及发芽和突触丧失活动。与神经元动作电位和神经元投射发育有关的SCP在21天时增加。总而言之，我们的结果揭示了一个临床相关的SCI小鼠模型，该模型概括了ApoE基因型对携带这些等位基因的个体SCI后功能的影响，并表明ApoE4动物恢复较差的潜在机制涉及神经胶质激活以及发芽和突触丧失活动。