PMID- 29618365 OWN - NLM STAT- MEDLINE DCOM- 20181109 LR - 20220716 IS - 1750-1326 (Electronic) IS - 1750-1326 (Linking) VI - 13 IP - 1 DP - 2018 Apr 4 TI - Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury. PG - 17 LID - 10.1186/s13024-018-0249-5 [doi] LID - 17 AB - BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated. METHODS: We exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI. RESULTS: In C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight-junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI. We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice. CONCLUSIONS: These data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI. FAU - Main, Bevan S AU - Main BS AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Villapol, Sonia AU - Villapol S AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Sloley, Stephanie S AU - Sloley SS AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Barton, David J AU - Barton DJ AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Parsadanian, Maia AU - Parsadanian M AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Agbaegbu, Chinyere AU - Agbaegbu C AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Stefos, Kathryn AU - Stefos K AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - McCann, Mondona S AU - McCann MS AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Washington, Patricia M AU - Washington PM AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Rodriguez, Olga C AU - Rodriguez OC AD - Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, 20057, USA. FAU - Burns, Mark P AU - Burns MP AD - Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. mpb37@georgetown.edu. AD - Department of Neuroscience, Georgetown University Medical Center, New Research Building-EG11, 3970 Reservoir Rd, NW, Washington, D.C, 20057, USA. mpb37@georgetown.edu. LA - eng GR - R03 NS095038/NS/NINDS NIH HHS/United States GR - R01 NS081068/NS/NINDS NIH HHS/United States GR - T32 NS041218/NS/NINDS NIH HHS/United States GR - The Advanced Rehabilitation Research and Training Program (90AR5005)/U.S. Department of Health and Human Services (US)/International GR - R01NS067417/NS/NINDS NIH HHS/United States GR - R03 NS067417/NS/NINDS NIH HHS/United States GR - R01 NS107370/NS/NINDS NIH HHS/United States GR - R03NS095038/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180404 PL - England TA - Mol Neurodegener JT - Molecular neurodegeneration JID - 101266600 RN - 0 (Apolipoprotein E3) RN - 0 (Apolipoprotein E4) SB - IM MH - Animals MH - Apolipoprotein E3/metabolism MH - Apolipoprotein E4/*metabolism MH - Blood-Brain Barrier/*pathology MH - Brain Injuries, Traumatic/*metabolism/*pathology MH - Capillary Permeability/physiology MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic PMC - PMC5885297 OTO - NOTNLM OT - Apolipoprotein E OT - Blood brain barrier OT - CD31 OT - Lectin OT - MMP-9 OT - Neurovascular unit OT - Pericyte OT - TBI COIS- AUTHORS' INFORMATION: OCR is from the Department of Oncology, Georgetown University Medical Center, Washington, DC, 20057, USA. All other authors are in the Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, 20057, USA. ETHICAL APPROVAL AND CONSENT TO PARTICIPATE: All animal research was ethically approved by the Georgetown University Animal Care and Use Committee. Experiments adhered to guidelines from the Guide for the Care and Use of Laboratory Animals, U.S. Department of Health and Human Services. Human subjects' consent to participate is not applicable. CONSENT FOR PUBLICATION: All contributing authors have given their consent for the publication of this study. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/04/06 06:00 MHDA- 2018/11/10 06:00 PMCR- 2018/04/04 CRDT- 2018/04/06 06:00 PHST- 2017/08/01 00:00 [received] PHST- 2018/03/21 00:00 [accepted] PHST- 2018/04/06 06:00 [entrez] PHST- 2018/04/06 06:00 [pubmed] PHST- 2018/11/10 06:00 [medline] PHST- 2018/04/04 00:00 [pmc-release] AID - 10.1186/s13024-018-0249-5 [pii] AID - 249 [pii] AID - 10.1186/s13024-018-0249-5 [doi] PST - epublish SO - Mol Neurodegener. 2018 Apr 4;13(1):17. doi: 10.1186/s13024-018-0249-5.