Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice
Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice
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DOI：
10.1523/jneurosci.2281-14.2014
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发表时间：
2014-10-15
影响因子：
5.3
通讯作者：
Huang, Yadong
中科院分区：
文献类型：
--
作者：
Knoferle, Johanna;Yoon, Seo Yeon;Huang, Yadong
载脂蛋白（apo）E4在许多类型的脑细胞中表达，与人类学习和记忆的年龄依赖性下降有关，是AD的主要遗传风险因素。为了确定apoE4的有害作用是否取决于其细胞来源，我们建立了人apoE基因敲入小鼠模型，其中人APOE基因在星形胶质细胞、神经元或GABA能中间神经元中被条件性删除。在这里，我们报告，星形胶质细胞中apoE4的缺失并不能保护老年小鼠免受apoE4诱导的GABA能中间神经元丢失和学习记忆缺陷。相比之下，神经元中apoE4的缺失确实可以保护老年小鼠免受这两种缺陷的影响。此外，GABA能中间神经元中apoE4的缺失足以获得类似的保护。这项研究表明，内源性产生的apoE4对GABA能中间神经元的有害作用，导致小鼠的学习和记忆缺陷，并为apoE4相关的AD药物开发提供了新的靶点。
Apolipoprotein (apo) E4 is expressed in many types of brain cells, is associated with age-dependent decline of learning and memory in humans, and is the major genetic risk factor for AD. To determine whether the detrimental effects of apoE4 depend on its cellular sources, we generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Here we report that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.