title: Apolipoprotein E Regulates Injury-Induced Activation of Hippocampal Neural Stem and Progenitor Cells.
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.
authors.affiliation: 1 Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
authors.forename: Sue
authors.initials: S
authors.lastname: Hong
authors.affiliation: 1 Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Washington
authors.affiliation: 1 Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
authors.forename: Ahleum
authors.initials: A
authors.lastname: Kim
authors.affiliation: 2 Key Laboratory of Animal Models and Human Disease Mechanisms , Chinese Academy of Sciences, Kunming, Yunnan, China .
authors.forename: Cui-Ping
authors.initials: CP
authors.lastname: Yang
authors.affiliation: 1 Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
authors.forename: Tzong-Shiue
authors.initials: TS
authors.lastname: Yu
authors.affiliation: 1 Departments of Pediatrics and Pathology and Cell Biology, Columbia University College of Physicians and Surgeons , New York, New York.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kernie
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D001057:Apolipoproteins E
keywords: apolipoprotein E; hippocampus; neural stem/progenitor cells; neurogenesis; traumatic brain injury