GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice

Abstract

SUMMARY Apolipoprotein (apo) E has important and diverse functions in neurobiology, and apoE4 is the major known genetic risk factor for Alzheimer’s disease. Here we report that adult neural stem/progenitor cells (NSCs) express apoE. In apoE knockout mice, neurogenesis in the hippocampus was ~60% lower than in wildtype mice, and most newborn cells developed into astrocytes rather than into neurons as in wildtype mice. This impairment was not observed in human apoE3 knock-in mice. In apoE4 knock-in mice, however, the maturation and dendritic development of newborn hippocampal neurons was significantly impaired as a result of apoE4 and its fragment-caused GABAergic interneuron dysfunction. This impairment was fully rescued by treatment with a GABAA receptor potentiator. These findings demonstrate the importance of apoE in adult hippocampal neurogenesis and show that apoE4 inhibits hippocampal neurogenesis by impairing neuronal maturation mediated by GABA signaling.

Cognitive Deficits and Disruption of Neurogenesis in a Mouse Model of Apolipoprotein E4 Domain Interaction

“…A study more relevant to ours showed that proliferation is also increased in the hippocampus of apoE4 mice relative to apoE3 mice, whereas maturation is delayed, and overall survival is decreased (99). Taken together, these data suggest that apoE4 domain interaction modeled in the Arg-61 mice may be sufficient to cause the disruption in neurogenesis as seen in the apoE4 mice.…”

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…Specifically, Ab modifies the balance between excitatory and inhibitory inputs on adult-born neurons (Sun et al 2009). Furthermore, risk genes for AD, such as the apolipopotein E, may have a detrimental effect on adult hippocampal neurogenesis as a result of altered signaling that promotes glial differentiation at the expense of neurogenesis (Li et al 2009). …”

ApoE is required for maintenance of the dentate gyrus neural progenitor pool

“…We previously generated and extensively characterized transgenic mice expressing enhanced green fluorescent protein (GFP) specifically within neural stem/progenitor cells (NSPCs) under the control of the neural progenitor-specific form of the nestin promoter and enhancer (Chen et al, 2009;Gritti and Bonfanti, 2007;Li et al, 2009;Li et al, 2008;Miles and Kernie, 2008;Shi et al, 2007;Yu et al, 2005;Yu et al, 2008). In addition, we recently demonstrated that ApoE expression increases dramatically from postnatal day (P) 7 to one month of age in GFP-expressing neural progenitor cells within the subgranular zone of the dentate gyrus (Gilley et al, 2011).…”

“…ApoE has long been implicated in a variety of neurodegenerative processes that affect hippocampal function. Recent data demonstrate that it also has dentate gyrusspecific effects, including directing progenitor fate towards astrocytic lineages (Bu, 2009;Li et al, 2009). This present work demonstrates that ApoE actually plays a dual role in dentate gyrus development.…”