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Published Online: 10 February 2016

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

Publication: Journal of Neurotrauma
Volume 33, Issue Number 4


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, ApoE 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 ApoE 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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Published In

cover image Journal of Neurotrauma
Journal of Neurotrauma
Volume 33Issue Number 4February 15, 2016
Pages: 362 - 374
PubMed: 25905575


Published in print: February 15, 2016
Published online: 10 February 2016
Published ahead of print: 11 June 2015
Published ahead of production: 23 April 2015


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Sue Hong
Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.
Patricia M. Washington
Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.
Ahleum Kim
Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.
Cui-Ping Yang
Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming, Yunnan, China.
Tzong-Shiue Yu
Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.
Steven G. Kernie
Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York.


Address correspondence to:Steven G. Kernie, MDColumbia University College of Physicians and Surgeons3959 Broadway, CHN 10-24New York, NY 10032E-mail: [email protected]

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