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

J Neurotrauma. 2016 Feb 15;33(4):362-74. doi: 10.1089/neu.2014.3860. Epub 2015 Jun 11.

Abstract

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.

Keywords: apolipoprotein E; hippocampus; neural stem/progenitor cells; neurogenesis; traumatic brain injury.

MeSH terms

  • Animals
  • Apolipoproteins E / physiology*
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Female
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Neurogenesis / physiology*
  • Stem Cells / metabolism
  • Stem Cells / pathology

Substances

  • Apolipoproteins E