Abstract WP103: ABCA1/HDL Signaling Pathway Mediates White Matter Remodeling and Improves Functional Outcome After Stroke

Abstract

The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the formation of brain HDL cholesterol, mainly from astrocytes. Specific brain ABCA1 deficient (ABCA1 -B/-B ) mice exhibit reduced HDL levels in brain tissue and cerebrospinal fluid, as well as increases in white matter (WM) damage and neurological deficits after stroke. We tested the hypothesis, that treatment of stroke in ABCA1 -B/-B mice with intraventricularly infused HDL increases WM remodeling in the ischemic brain and attenuates ABCA1 -B/-B induced deficits after stroke. Method: Adult male ABCA1 -B/-B mice were subjected to permanent right distal middle cerebral artery occlusion (dMCAo), and were intraventricularly infused with PBS or recombinant human HDL3 (rhHDL3, 25μg in 100μl PBS) by transplanting a micro-osmotic pump (D1002, 0.25 μl/h for 14 days, Alzet) into the right lateral ventricle starting 24h after dMCAo. Animals were sacrificed 21 days after dMCAo. In vitro primary cortical neuron (PCN) culture derived from C57BL/6 and ABCA1 -B/-B embryos and axonal outgrowth measurements were also employed. Results: 1) There were no ischemic lesion volume changes between the two groups. 2) rhHDL3-infused ABCA1 -B/-B stroke mice exhibited significantly increased WM-remodeling identified by increased level of myelin basic protein, increased densities of myelin and axons, increased number of oligodendrocytes and oligodendrocyte progenitor cells in the ischemic boundary zone, as well as improved functional outcome compared with PBS-infused ABCA1 -B/-B stroke mice (p<0.05, n=8/group). 3) HDL (40 or 80μg/ml) treatment in ABCA1 -B/-B -PCNs significantly increased axonal outgrowth compared to non-treatment control. Treatment of C57BL/6-PCNs with astrocyte-conditioned media derived from ABCA1 -B/-B embryos significantly decreased axonal outgrowth compared to treatment with astrocyte-conditioned media derived from ABCA1 floxed-control embryos. However, ABCA1 -B/-B -astrocyte-conditioned media combination with HDL treatment significantly increased C57BL/6-PCN axonal outgrowth compared to treatment with ABCA1 -B/-B -astrocyte-conditioned media alone. Conclusion: ABCA1/HDL pathway may contribute to WM-remodeling as well as functional recovery after stroke.