Abstract W P205: Specific Deficiency of Brain ABCA1 Increases Inflammation and White Matter Damage and Worsens Functional Outcome After Stroke

Abstract

Background: ATP-binding cassette transporter A1 (ABCA1) plays a critical role in HDL-cholesterol production and has been identified as a potent anti-inflammatory molecule in macrophages and other immune cells. However, direct experimental support of this hypothesis in cerebral ischemia is lacking. Using specific deficiency of brain ABCA1 mice, we therefore tested whether ABCA1 plays a role in neuro-inflammation and white matter damage after stroke. Methods: Adult male brain ABCA1 knockout control (floxed, ABCA1 fl/fl ) and brain ABCA1 knockout (floxed, nestin-Cre positive, ABCA1 -B/-B ) mice were subjected to permanent extraluminal distal middle cerebral artery occlusion (dMCAo) by transcranial ligation of distal MCA with a 10-0 filament. Animals were sacrificed 7 days after MCAo. A battery of functional outcomes, infarct volume, and immunostaining for analysis of inflammation and white matter damage were performed. Results: There is no significant difference in blood level of total cholesterol, triglyceride and HDL before and after MCAo between ABCA1 -B/-B and ABCA1 fl/fl mice. However, ABCA1 -B/-B mice showed: 1) increased infarct volume (21.67%±2.95%, n=14, p=0.022) compared with ABCA1 fl/fl (11.57%±1.58%, n=9); 2) decreased functional outcome evaluated by the adhesive removal and basket tests performed at 1, 3 and 7 days after MCAo (p<0.05); 3) increased inflammation in the ischemic brain, including: (a) decreased the number of CD163 (M2 macrophage marker, anti-inflammatory) positive cells, but an increased the ratio of ED1 (M1 macrophage marker, pro-inflammatory)/CD163 positive cells; ( b ) increased matrix metalloproteinase-9 (MMP-9) expression measured by immunostaining; ( c ) increased number of NFkB positive cells; 4) increased white matter damage: decreased density of Luxol Fast Blue (myelin marker, p<0.01) and Bielshowsky silver (axon marker, p<0.05) compared to ABCA1fl/fl mice. Conclusions: Specific deficiency of brain ABCA1 increases inflammation and white matter damage in the ischemic brain, which may play important roles in increasing infarct volume and decreasing functional outcome after stroke. These data indicate that ABCA1 plays an important role in inhibiting neuro-inflammation in the ischemic brain after stroke.