ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke

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 (ABCA1^fl/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/-B stroke 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 ABCA1^fl/fl ischemic mice, ABCA1^-B/-B ischemic 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 ABCA1^fl/fl ischemic 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/-B ischemic 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 ABCA1^fl/fl embryos, but not in neurons derived from ABCA1^-B/-B embryos. HDL treatment (80 μg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1^-B/-B embryos.

ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.