Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice.
Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice.
复制标题
DOI：
10.1038/s42003-021-02841-4
复制
发表时间：
2021-11-18
影响因子：
5.9
通讯作者：
Kernie SG
中科院分区：
文献类型：
--
作者：
Yu TS;Tensaouti Y;Stephanz EP;Chintamen S;Rafikian EE;Yang M;Kernie SG
载脂蛋白E（ApoE）基因的多态性赋予迟发性阿尔茨海默病（AD）发展的主要遗传风险，并预测创伤性脑损伤（TBI）后的结局。成年海马神经发生的改变长期以来与AD的发展和TBI后的恢复相关，并且已知ApoE在此过程中发挥作用。为了确定ApoE可能如何影响海马损伤诱导的神经发生，我们产生了一个条件性敲除系统，其中功能性ApoE从星形胶质细胞损伤前消融。虽然在小鼠TBI之前成功消融ApoE，但我们观察到新生神经元中棘的发育减弱。有趣的是，具有双重打击（即损伤和ApoE在星形胶质细胞中条件性失活）的动物在海马依赖性Morris水迷宫测试中表现出最明显的损伤，在获得和逆转训练试验后均未能表现出空间记忆。相比之下，无损伤的条件性基因敲除小鼠显示损伤，但仅在测试的逆转阶段，表明星形胶质细胞ApoE缺陷和创伤性脑损伤对AD样表型的累积效应。总之，这些发现表明星形胶质细胞ApoE是创伤性脑损伤后功能性损伤诱导的神经发生所必需的。Tzong-Shiue Yu等人评估了星形胶质细胞ApoE对小鼠创伤性脑损伤（TBI）后海马神经发生和行为的影响。他们的结果表明，出生后星形胶质细胞APOE的消融降低了新生齿状回神经元和认知能力的树突复杂性，为APOE在TBI后损伤诱导的神经发生中的作用提供了进一步的见解。
Polymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer’s disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we generated a conditional knockout system whereby functional ApoE from astrocytes was ablated prior to injury. While successfully ablating ApoE just prior to TBI in mice, we observed an attenuation in the development of the spines in the newborn neurons. Intriguingly, animals with a double-hit, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury. Tzong-Shiue Yu et al. assess the impact of astrocytic ApoE on hippocampal neurogenesis and behavior after traumatic brain injury (TBI) in mice. Their results suggest that postnatal ablation of astrocytic APOE reduces dendritic complexity in newborn dentate gyrus neurons and cognitive ability, providing further insight into a role for APOE in injury-induced neurogenesis following TBI.