GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knock-in Mice

By Gang Li, Nga Bien-Ly, Y. Andrews-Zwilling, Qin Xu, Aubrey Bernardo, Karen Ring, Brian Halabisky, Changhui Deng, Robert W. Mahley, Yadong Huang. 2009

284 citations recorded by the source corpus.

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.

Subfields: Developmental Neuroscience, Neurology, Physiology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Developmental Neuroscience

1. Yangling Mu
2. Fred H. Gage
3. Sarah L. Parylak
4. Sara B. Linker
5. T. Toda
6. L. Mucke
7. J. Palop
8. Hongjun Song

In Neurology

1. Yangling Mu
2. Fred H. Gage
3. David A. Bennett
4. L. Mucke
5. J. Palop
6. Hongjun Song
7. Wei Deng
8. James Bradley Aimone

In Physiology

1. L. Mucke
2. J. Palop
3. Fred H. Gage
4. David A. Bennett
5. Yangling Mu
6. D. Selkoe

Citations in the corpus

• The role of adult hippocampal neurogenesis in brain health and disease (2018, background): “Type2a, 2b Proliferation of NPs FGF2 [199], IGF-2 [198], EGF [200, 201], ERK5 [202], estrogen [29] Promoting differentiation Wnt [203–205], IGF-1 [206, 207], VEGF [193], BDNF/NT-3 [208], BMPs [192, 209] Inhibition of proliferation Cortisol [25, 28, 137], chronic opioid use [210], ApoE4 [39]”
• Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease (2013, background): “The close connectivity of APOE and GABA metabolism in the brain network may therefore have some bearing on the observation that GABA interneuron dysfunction is particularly severe in APOE4 carriers (Li et al., 2009).”
• Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks (2010, background): “Mouse models of apoE4, the main genetic risk factor for Alzheimer's disease, show prominent GABAergic dysfunction and impaired GABA release in the hippocampu”
• Adult hippocampal neurogenesis and its role in Alzheimer's disease (2011, methodology): “Potentiating GABAergic signaling restored neuronal maturation and neurogenesis in ApoE4-KI mice to normal levels [41].”