A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
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DOI：
10.1093/embo-reports/kvf124
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发表时间：
2002-07-01
期刊：
影响因子：
7.7
通讯作者：
Haass, C
中科院分区：
文献类型：
--
作者：
Geling, A;Steiner, H;Haass, C
通过阻断γ-分泌酶活性抑制淀粉样β-肽(Abeta)的产生是目前延缓阿尔茨海默病病理进展的最有前途的治疗策略之一。伽马分泌酶抑制剂明显通过干扰早老素(PS)功能来阻断Abeta的产生。除了是γ-分泌酶复合体的重要组成部分外，PS本身可能是一种具有γ-分泌酶活性的天冬氨酸蛋白酶，这不仅是产生Abeta所必需的，也是参与Notch信号转导的类似蛋白分解过程所必需的。在这里，我们证明了用已知的伽马分泌酶抑制剂处理斑马鱼胚胎会影响胚胎发育，在形态、分子和生化水平上与Notch信号缺陷难以区分。这表明伽马分泌酶抑制剂在任何依赖Notch的细胞命运决定中都会产生严重的副作用，并表明斑马鱼是一个理想的脊椎动物系统，可以在体内条件下验证选择性影响Abeta产生而不是Notch信号的化合物。
Inhibition of amyloid beta-peptide (Abeta) production by blocking gamma-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. gamma-secretase inhibitors apparently block Abeta generation via interference with presenilin (PS) function. Besides being an essential component of the gamma-secretase complex, PS itself may be an aspartyl protease with gamma-secretase activity, which is not only required for Abeta production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known gamma-secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side-effects of gamma-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Abeta production, but not Notch signaling, under in vivo conditions.