title: Deficiency of brain ATP-binding cassette transporter A-1 exacerbates blood-brain barrier and white matter damage after stroke.
abstract: OBJECTIVE
  The ATP-binding cassette transporter A-1 (ABCA1) gene is a key target of the transcription factors liver X receptors. Liver X receptor activation has anti-inflammatory and neuroprotective effects in animal ischemic stroke models. Here, we tested the hypothesis that brain ABCA1 reduces blood-brain barrier (BBB) and white matter (WM) impairment in the ischemic brain after stroke.
  
  
  METHODS
  Adult brain-specific ABCA1-deficient (ABCA1(-B/-B)) and floxed-control (ABCA1(fl/fl)) mice were subjected to permanent distal middle cerebral artery occlusion and were euthanized 7 days after distal middle cerebral artery occlusion. Functional outcome, infarct volume, BBB leakage, and WM damage were analyzed.
  
  
  RESULTS
  Compared with ABCA1(fl/fl) mice, ABCA1(-B/-B) mice showed marginally (P=0.052) increased lesion volume but significantly increased BBB leakage and WM damage in the ischemic brain and more severe neurological deficits. Brain ABCA1-deficient mice exhibited increased the level of matrix metalloproteinase-9 and reduced the level of insulin-like growth factor 1 in the ischemic brain. BBB leakage was inversely correlated (r=-0.073; P<0.05) with aquaporin-4 expression. Reduction of insulin-like growth factor 1 and aquaporin-4, but upregulation of matrix metalloproteinase-9 expression were also found in the primary astrocyte cultures derived from ABCA1(-B/-B) mice. Cultured primary cortical neurons derived from C57BL/6 wild-type mice with ABCA1(-B/-B) astrocyte-conditioned medium exhibited decreased neurite outgrowth compared with culture with ABCA1(fl/fl) astrocyte-conditioned medium. ABCA1(-B/-B) primary cortical neurons show significantly decreased neurite outgrowth, which was attenuated by insulin-like growth factor 1 treatment.
  
  
  CONCLUSIONS
  We demonstrate that brain ABCA1 deficiency increases BBB leakage, WM/axonal damage, and functional deficits after stroke. Concomitant reduction of insulin-like growth factor 1 and upregulation of matrix metalloproteinase-9 may contribute to brain ABCA1 deficiency-induced BBB and WM/axonal damage in the ischemic brain.
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.). tcui@neuro.hfh.edu jieli@neuro.hfh.edu.
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Karasinska
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Ruizhuo
authors.initials: R
authors.lastname: Ning
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.).
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (X.C., M.C., A.Z., Y.C., R.N., Y.Z., J.C.); Department of Physics, Oakland University, Rochester, MI (M.C.); Neural Protection and Regeneration section, Center for Neuropsychiatric Research, National Institute on Drug Abuse, NIH, Baltimore, MD (Y.W.); and Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (J.M.K.). tcui@neuro.hfh.edu jieli@neuro.hfh.edu.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020521:Stroke / Q000097:blood* / Q000235:genetics*; D016896:Treatment Outcome; D066127:White Matter / Q000473:pathology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D007334:Insulin-Like Growth Factor I; D020780:Matrix Metalloproteinase 9; C577833:Abca1 protein, mouse; C519530:insulin-like growth factor-1, mouse; C501830:Mmp9 protein, mouse
keywords: ATP binding cassette transporter A-1; aquaporin 4; blood–brain barrier; insulin-like growth factor binding protein 1; stroke; white matter