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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.

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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