Apolipoprotein E Regulates Injury-Induced Activation of Hippocampal Neural Stem and Progenitor Cells

Significance Statement

ApoE is a gene that has long been known to influence cognitive function in humans with traumatic brain injury, although how this occurs is unclear.  Apolipoprotein E (ApoE) isoforms in humans independently predict outcome severity after traumatic brain injury and are strong predictors for the development of Alzheimer disease in the absence of injury. Apolipoprotein E has widespread brain expression, but it remains unclear how it may contribute to brain dysfunction after injury.  Within the brain, Apolipoprotein E is expressed primarily in astrocytes and regulates cholesterol distribution within both astrocytes and neurons.  We previously found Apolipoprotein E to be one of the most strongly upregulated genes in the developing dentate gyrus, whereby its expression increases with age specifically within neural progenitors in the hippocampus, a critical area of the brain that regulates learning and memory and is often damaged following traumatic brain injury (Gilley et al., 2011).  We subsequently demonstrated that Apolipoprotein E impairs adult hippocampal neurogenesis by negatively regulating progenitor proliferation (Yang et al., 2011).  The purpose of the current study was to determine whether Apolipoprotein E influences injury-induced hippocampal neurogenesis, a process known to mediate self-repair following traumatic brain injury (Blaiss et al., 2011).  This study demonstrates how Apolipoprotein E deficiency and expression of human Apolipoprotein E isoforms in mice impairs progenitor proliferation following injury.  This suggests that the role of Apolipoprotein E on progenitors may at least partially explain its role in modifying recovery following traumatic brain injury by directly affecting injury-induced neurogenesis.

Gilley, J.A., Yang, C.P., and Kernie, S.G. (2011). Developmental profiling of postnatal dentate gyrus progenitors provides evidence for dynamic cell-autonomous regulation. Hippocampus 21, 33-47.

Yang, C.P., Gilley, J.A., Zhang, G., and Kernie, S.G. (2011). ApoE is required for maintenance of the dentate gyrus neural progenitor pool. Development 138, 4351-4362.

Blaiss, C.A., Yu, T.S., Zhang, G., Chen, J., Dimchev, G., Parada, L.F., Powell, C.M., and Kernie, S.G. (2011). Temporally specified genetic ablation of neurogenesis impairs cognitive recovery after traumatic brain injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 4906-4916.


Figure legend

Hippocampal dentate gyrus in transgenic mice expressing GFP in hippocampal progentors (green) and Apolipoprotein E in GFAP-expressing astrocytes and progenitors (red).

Apolipoprotein E Regulates Injury-Induced Activation Hippocampal Neural Stem Progenitor Cells. Global Medical Discovery

















Journal Reference 

J Neurotrauma. 2015 Jun 11.

Hong S1, Washington PM1, Kim A1, Yang CP2, Yu TS1, Kernie SG1.

[expand title=”Show Affiliations”]
  1. Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
  2. Key Laboratory of Animal Models and Human Disease Mechanisms , Chinese Academy of Sciences, Kunming, Yunnan, China .


Partial recovery from even severe traumatic brain injury (TBI) is ubiquitous and occurs largely through unknown mechanisms. Recent evidence suggests that hippocampal neural stem/progenitor cell (NSPC) activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following TBI. Apolipoprotein E (ApoE) regulates postnatal neurogenesis in the hippocampus and is therefore a putative mediator of injury-induced neurogenesis. Further, Apolipoprotein E isoforms in humans are associated with different cognitive outcomes following TBI. To investigate the role of ApoE in injury-induced neurogenesis, we exposed wild-type, ApoE-deficient, and human Apolipoprotein E isoform-specific (ApoE3 and ApoE4) transgenic mice crossed with nestin-green fluorescent protein (GFP) reporter mice to controlled cortical impact (CCI) and assessed progenitor activation at 2 d post-injury using unbiased stereology. GFP+ progenitor cells were increased by approximately 120% in the ipsilateral hippocampus in injured wild-type mice, compared with sham mice (p<0.01). Co-localization of GFP+ cells with bromodeoxyrudine (BrdU) to label dividing cells indicated increased proliferation of progenitors in the injured hippocampus (p<0.001). This proliferative injury response was absent in ApoE-deficient mice, as no increase in GFP+ cells was observed in the injured hippocampus, compared with sham mice, despite an overall increase in proliferation indicated by increased BrdU+ cells (86%; p<0.05). CCI-induced proliferation of GFP+ cells in both ApoE3 and ApoE4 mice but the overall response was attenuated in ApoE4 mice due to fewer GFP+ cells at baseline. We demonstrate that ApoE is required for injury-induced proliferation of NSPCs after experimental TBI, and that this response is influenced by human APOE genotype.

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