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Logo of jbcThe Journal of Biological Chemistry
 
From:
Published online 2014 October 20. doi: 10.1074/jbc.M114.608091

FIGURE 7.

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Effects of pharmacological inhibition of Syk on Aβ clearance across the BBB and on brain Aβ levels in Tg PS1/APPsw mice. A, BAY61-3606 stimulates the transport of Aβ(1–42) in an in vitro BBB model employing human brain microvascular endothelial cells. The histogram represents the apparent permeability of Aβ(1–42) calculated for a period of 90 min in response to a dose range of BAY61-3606 and depicts the transport of Aβ(1–42) from the basolateral (brain) to the apical (blood) compartment of the BBB model. Results are expressed as the percentage of Aβ(1–42) apparent permeability observed in the control conditions. ANOVA show a significant main effect of BAY61-3606 (p < 0.05) on Aβ(1–42) levels transported to the apical side of the BBB model. Post hoc comparisons reveal statistically significant differences in the amount of Aβ(1–42) transported from the basolateral (brain side) to the apical side (blood side) for human brain microvascular endothelial cells treated with 5 μm BAY61-3606 (p < 0.05) showing that pharmacological inhibition of Syk activity stimulates the transport of Aβ(1–42) across the BBB in this in vitro model. * indicates statistically significant differences compared with the control conditions. B, BAY61-3606 increases the clearance of human Aβ(1–42) across the BBB in vivo. ANOVA shows a significant main effect of BAY61-3606 on plasma human Aβ(1–42) (p < 0.03) detected following an intracranial injection of the peptide. Post hoc comparisons reveal a statistically significant difference in plasma human Aβ(1–42) between vehicle-treated mice and mice treated with 4 mg/kg BAY61-3606 (p < 0.05) showing that at this dose BAY61-3606 stimulates the clearance of Aβ(1–42) across the BBB in vivo. * indicates statistically significant differences compared with the vehicle treatment conditions. C, effects of pharmacological inhibition of Syk with BAY61-3606 on brain Aβ38, Aβ40, and Aβ42 levels in Tg PS1/APPsw mice. Histogram representing the amount of detergent-soluble Aβ38, Aβ40, and Aβ42 detected in the brains of vehicle and BAY61-3606-treated Tg PS1/APPsw mice. A significant reduction in brain detergent-soluble Aβ38 (p < 0.01), Aβ40 (p < 0.01), and Aβ42 (p < 0.01) levels was observed in BAY61-3606-treated Tg PS1/APPsw compared with vehicle-treated mice (placebo). D, histogram representing the amount of detergent-insoluble Aβ38, Aβ40, and Aβ42 detected in the brains of vehicle (placebo) and BAY61-3606-treated Tg PS1/APPsw mice. A significant reduction in brain detergent-insoluble Aβ38 (p < 0.01), Aβ40 (p < 0.01), and Aβ42 (p < 0.05) levels was observed in BAY61-3606-treated Tg PS1/APPsw compared with vehicle-treated mice (placebo).

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