Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-α-converting enzyme protease activity
Stroke-induced subventricular zone proliferation is promoted by tumor necrosis factor-α-converting enzyme protease activity
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DOI：
10.1038/sj.jcbfm.9600390
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发表时间：
2007-04-01
影响因子：
6.3
通讯作者：
Chopp, Michael
中科院分区：
文献类型：
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作者：
Katakowski, Mark;Chen, Jieli;Chopp, Michael
脑卒中会诱导成年啮齿动物大脑中室下区（SVZ）神经祖细胞的增殖。肿瘤坏死因子-α 转换酶 (TACE) 蛋白水解作用会释放淀粉样前体蛋白 (APP) 的非淀粉样蛋白形成可溶性胞外域，并且是肿瘤坏死因子-α (TNF α) 的转化酶。由此产生的 APP 和 TNF α 的可溶性肽对于 SVZ 的神经祖细胞具有促有丝分裂作用。因此，我们假设 TACE 蛋白水解在中风诱导的神经发生中发挥作用。使用激光捕获显微切割，我们发现缺血脑的 SVZ 细胞中 TACE 转录增加。免疫组织化学显示 SVZ 神经母细胞中 TACE 蛋白表达上调。脑室内输注肿瘤坏死因子-α 蛋白酶抑制剂-2 (TAPI-2) 可减少大脑中动脉闭塞大鼠 SVZ 细胞中溴脱氧尿苷的掺入。此外，来自缺血脑的原代培养物 SVZ 神经球过度表达 TACE 及其底物 APP 和 TNF-α。与非缺血对照相比，这些细胞增殖更快，具有更高的 TACE 蛋白酶依赖性 α 分泌酶活性，并释放更多可溶性 APP 和 TNF α。此外，TAPI-2 减少了 SVZ 神经母细胞在体外从 SVZ 外植体中的迁移。这些发现表明 TACE 蛋白水解是中风诱导的 SVZ 祖细胞神经发生的促进剂，并表明这种蛋白酶活性可能代表中风恢复的一个有吸引力的治疗靶点。
Cerebral stroke induces proliferation of subventricular zone (SVZ) neural progenitor cells in adult rodent brain. Tumor necrosis factor-alpha-converting enzyme (TACE) proteolysis sheds the nonamyloidogenic soluble ectodomain of the amyloid precursor protein (APP) and is a convertase for tumor necrosis factor-alpha (TNF alpha). The resulting soluble peptides of APP and TNF alpha are mitogenic for neural progenitor cells of the SVZ. Therefore, we hypothesized a role for TACE proteolysis in stroke-induced neurogenesis. Using laser-capture microdissection, we found TACE transcription was increased in SVZ cells of ischemic brain. Immunohistochemistry revealed TACE protein was upregulated in SVZ neuroblasts. Intraventricular infusion of tumor necrosis factor-alpha protease inhibitor-2 (TAPI-2) decreased bromodeoxyuridine incorporation in SVZ cells of rats subjected to middle cerebral artery occlusion. Furthermore, primary culture SVZ neurospheres from ischemic brain overexpress TACE and its substrates APP and TNF-alpha. These cells proliferated more rapidly, possessed increased TACE protease-dependent alpha-secretase activity, and released more soluble APP and TNF alpha compared with nonischemic control. In addition, TAPI-2 reduced SVZ neuroblast migration out of SVZ explants in vitro. These findings indicate TACE proteolysis as a promoter of stroke-induced SVZ progenitor cell neurogenesis, and suggest this protease activity may represent an attractive therapeutic target for stroke recovery.