Abstract TP103: Cholesterol Transporters Abca1 and Apoe Mediate Grey/White Matter Remodeling and Neurogenesis/Oligodendrogenesis After Stroke

Abstract

The ATP-binding cassette transporter-A1 (ABCA1) and apolipoprotein-E (ApoE) are major cholesterol transporters in the brain. ABCA1 effluxes cholesterol and phospholipids to extra-cellular, and ApoE transport cholesterol and lipid back into cells. Brain-specific ABCA1-deficient (ABCA1 -B/-B ) 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/-B mice were subjected to distal middle cerebral artery occlusion (dMCAo) and were intraventricularly-infused 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/-B and ABCA1-floxed control (ABCA1 fl/fl ) 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<0.05, n=11/group). In vitro data show that: 1) ABCA1 -B/-B decreased axonal-outgrowth and ApoE-treatment (2, 4 and 8 μg/ml) significantly attenuated ABCA1 -B/-B -induced reduction in axonal-outgrowth; 2) ABCA1 -B/-B decreased OPC proliferation and survival compared with ABCA1 fl/fl -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.