Cholesterol transporters ABCA1 and APOE mediate grey/white matter remodeling and neurogenesis/oligodendrogenesis after stroke

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The ATP-binding cassette transporter-A1 (ABCA1) and apolipoprotein-E (ApoE) are major cholesterol transporters in the brain. ABCA1-B/-Beffluxes cholesterol and phospholipids to extra-cellular, and ApoE transport cholesterol and lipid back into cells. Brainspecific ABCA1-deficient (ABCA1 ) mice exhibit reduced ApoE level in brain and cerebrospinal-fluid (CSF), and increased white matter damage and neurological deficits after stroke. Hypothesis: ApoE-treatment increases grey/white matter remodeling and neurogenesis/oligodendrogenesis in the ischemic brain in ABCA1-B/-B-stroke mice. Methods: Adult ABCA1-B/-Bmice were subjected to distal middle cerebral artery occlusion (dMCAo) and were intraventricularlyinfused with recombinant human ApoE2 (rhApoE2, 25μg in artificial-CSF) or artificial-CSF as vehicle-control by transplanting a micro-osmotic pump into the right lateral-ventricle starting 24h after dMCAo until sacrifice 14 days after dMCAo. Primary cultured cortical neurons (PCNs) and oligodendrocyte progenitor cells (OPCs) derived from ABCA1-B/-Band ABCA1-floxed control (ABCA1 ) mice were employed, and the PCN-axonal outgrowth and OPC proliferation/death were investigated. Results: No changes in the lesion volume between ABCA1-B/-B+CSF and ABCA1-B/-B+rhApoE2 mice were found. Compared with ABCA1-B/-B+CSF mice, the ABCA1-B/-B+rhApoE2 mice exhibit: 1) increased CSF ApoE level and improved functional outcome 7 and 14 days after dMCAo; 2) increased grey matter and white matter density in the ischemic boundary zone; 3) increased neurogenesis in the subventricular zone and oligodendrogenesis in the corpus collosum in the ischemic brain (p-B/-Bdecreased axonal-outgrowth and ApoE-treatment (2, 4 and 8 μg/ml) significantly attenuated ABCA1-B/-B-induced reduction in axonal-outgrowth; 2) ABCA-B/-Bdecreased OPC proliferation and survival compared with ABCA1-B/-B-OPCs and ApoE treatment increased OPC proliferation and OPC survival in primary cultured ABCA1-B/-B-OPCs. Conclusion: ABCA1/ApoE contributes to grey and white matter remodeling, increases neurogenesis and oligodendrogenesis as well as improves functional recovery after stroke.




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