title: ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke.
abstract: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke.
  
  
  
  Middle-aged male specific brain ABCA1-deficient (ABCA1-B/-B) and floxed-control (ABCA1fl/fl) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1-B/-Bstroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo.
  
  
  
  No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1fl/flischemic mice, ABCA1-B/-Bischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1fl/flischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1-B/-Bischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-B/-B-induced deficits. In vitro, GW3965 treatment (5 μM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1fl/flembryos, but not in neurons derived from ABCA1-B/-Bembryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1-B/-Bembryos.
  
  
  
  ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.). xcui1@hfhs.org.
authors.forename: Xu
authors.initials: X
authors.lastname: Cui
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Rongwen
authors.initials: R
authors.lastname: Li
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Julie
authors.initials: J
authors.lastname: Landschoot-Ward
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Poornima
authors.initials: P
authors.lastname: Venkat
authors.affiliation: From the Department of Neurology, Henry Ford Health System, Detroit, MI (X.C., M.C., Z.Z., R.L., A.Z., J.L.-W., P.V., J.C.); and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000096:biosynthesis* / Q000172:deficiency*; D000818:Animals; D001057:Apolipoproteins E / Q000096:biosynthesis*; D001565:Benzoates / Q000008:administration & dosage*; D001596:Benzylamines / Q000008:administration & dosage*; D008076:Cholesterol, HDL / Q000008:administration & dosage; D006801:Humans; D057967:Infusions, Intraventricular; D008075:Lipoproteins, HDL / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; C577833:Abca1 protein, mouse; C473027:GW 3965; C025121:apolipoprotein E-rich HDL
keywords: ATP-binding cassette transporter A1; apolipoprotein E; high-density lipoprotein; liver-X receptors; stroke; white matter