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首页> 外文期刊>CNS neuroscience & therapeutics. >The γ‐Secretase Blocker DAPT Reduces the Permeability of the Blood–Brain Barrier by Decreasing the Ubiquitination and Degradation of Occludin During Permanent Brain Ischemia
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The γ‐Secretase Blocker DAPT Reduces the Permeability of the Blood–Brain Barrier by Decreasing the Ubiquitination and Degradation of Occludin During Permanent Brain Ischemia

机译：γ-secretase阻断剂DAPT通过减少永久性脑缺血过程中闭合蛋白的泛素化和降解来降低血脑屏障的通透性

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Summary Background Tight junction protein degradation is a principal characteristic of the blood–brain barrier ( BBB ) damage that occurs during brain ischemia. Aims We investigated the mechanisms of occludin degradation that underlie permanent middle cerebral artery occlusion (p MCAO ) in rats. Methods and Results Western blot and C o‐immunoprecipitation data indicated ubiquitination and degradation of occludin in brain after p MCAO , which was consistent with ZO ‐1 degradation in penumbra regions as observed at 24 h after p MCAO . We further investigated candidate protease(s) responsible for the degradation of occludin during p MCAO . The intraventricular administration of γ‐secretase blocker DAPT significantly inhibited the p MCAO ‐induced neurovascular damage, whereas ALLM and Batimastat, which are inhibitors of calpain and metalloproteinase proteases, respectively, were less effective. Notably, we found that DAPT significantly inhibited BBB disruption in comparison with vehicle treatment, as assessed by Evans blue excretion. Interestingly, the confocal immunostaining revealed that activation of the E 3 ubiquitin ligase Itch is associated with degradation of occludin in brain microvessels following ischemia. Furthermore, our data demonstrate that the inhibition of γ‐secretase signaling and the itch‐mediated ubiquitination of occludin likely underlie the vasoprotective effect of DAPT after p MCAO . Conclusion The γ‐secretase blocker DAPT reduces the permeability of the BBB by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia, suggesting that γ‐secretase may represent a novel therapeutic target for preventing neurovascular damage.
机译：发明背景紧密连接蛋白降解是脑缺血期间发生的血脑屏障（BBB）损伤的主要特征。目的我们研究了大鼠大脑永久永久性大脑中动脉闭塞（p MCAO）背后的闭合蛋白降解机理。方法和结果Western blot和C o-免疫沉淀数据表明，p MCAO后脑内的蛋白和泛素降解，与p MCAO后24 h的半影区ZO -1降解一致。我们进一步研究了在p MCAO期间负责occludin降解的候选蛋白酶。脑室内给予γ-分泌酶阻滞剂DAPT可以显着抑制p MCAO诱导的神经血管损伤，而分别作为钙蛋白酶和金属蛋白酶抑制剂的ALLM和Batimastat效果较差。值得注意的是，我们发现与媒介物处理相比，DAPT可以显着抑制BBB破坏，如通过Evans蓝排泄物评估的那样。有趣的是，共聚焦免疫染色揭示了E 3泛素连接酶Itch的激活与缺血后脑微血管中occludin的降解有关。此外，我们的数据表明，γ-分泌酶信号转导的抑制和闭合蛋白由痒介导的泛素化可能是p MCAO后DAPT的血管保护作用的基础。结论γ-分泌酶阻断剂DAPT通过减少永久性脑缺血过程中occludin的泛素化和降解来降低BBB的通透性，这表明γ-分泌酶可能是预防神经血管损伤的一种新型治疗靶点。

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