Apolipoprotein E4 (APOE4) is expressed in many types of brain cells and is associated with age-dependent decline of learning and memory in humans. It is a major genetic risk factor for Alzheimer’s Disease. To determine whether the detrimental effects of APOE4 depend on its cellular sources, Knoferle and colleagues generated human APOE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. Deletion of APOE4 in astrocytes did not protect aged mice from APOE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of APOE4 in neurons protected aged mice from both deficits. Furthermore, deletion of APOE4 in GABAergic interneurons was sufficient to gain similar protection. The authors concluded that endogenously produced APOE4 has a detrimental effect on GABAergic interneurons that leads to learning and memory deficits in mice. It may be a novel target for Alzheimer-related drug development.
.
Knoferle J, Yoon SY, Walker D, Leung L, Gillespie AK, Tong LM, Bien-Ly N and Huang Y: Apolipoprotein E4 Produced in GABAergic Interneurons Causes Learning and Memory Deficits in Mice. J. Neuroscience 34(42): 14069-14078 (2014).
.
http://www.jneurosci.org/content/34/42/14069.abstract?etoc