Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice

作者：Knoferle Johanna; Yoon Seo Yeon; Walker David; Leung Laura; Gillespie Anna K; Tong Leslie M; Bien Ly Nga; Huang Yadong^*

来源：Journal of Neuroscience, 2014, 34(42): 14069-14078.

DOI：10.1523/JNEUROSCI.2281-14.2014

• apoE
• astrocyte
• conditional knock-out mice
• GABAergic interneuron
• learning and memory

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.

• 出版日期2014-10-15