Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain
Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain
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DOI：
10.1186/1750-1326-5-35
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发表时间：
2010-09-15
影响因子：
15.1
通讯作者：
Suzuki, Toshiharu
中科院分区：
文献类型：
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作者：
Kondo, Maho;Shiono, Maki;Suzuki, Toshiharu
背景：X11家族蛋白包括X11、X11样蛋白(X11L)和X11样蛋白2(X11L2)，它们与淀粉样β蛋白前体(APP)的胞浆结构域结合，调节APP的代谢。X11和X11L均在脑内特异表达，而X11L2在脑内普遍表达。X11L主要在兴奋性神经元中表达，而X11在抑制性神经元中强烈表达。针对X11、X11L或两者的体内基因敲除研究以及对X11或X11L转基因小鼠的研究都报告了X11家族蛋白抑制内源性APP和异位人类APP的淀粉样蛋白的形成过程，但有一个例外：X11、X11L或X11L2的敲除被发现抑制过表达人瑞典突变体APP(APPswe)和缺乏外显子9的突变型人PS1(PS1dE9)的转基因小鼠的淀粉样蛋白代谢。结果：为了证实X11L与小鼠脑内异位表达的人APP的相互作用，我们在两个同样缺乏X11L的人APP转基因小鼠中检测了人APP的淀粉样蛋白代谢。与本实验室和其他研究人员的报道一致，我们发现在缺乏X11L的情况下，人APP的淀粉样代谢增加。结论：X11L似乎有助于在体内抑制人APP在脑内的淀粉样蛋白加工，这一点已被先前使用几个具有不同遗传背景的人APP转基因株所证实。X11L似乎以类似于内源性小鼠APP新陈代谢的方式调节人类APP。
Background: X11-family proteins, including X11, X11-like (X11L) and X11-like 2 (X11L2), bind to the cytoplasmic domain of amyloid beta-protein precursor (APP) and regulate APP metabolism. Both X11 and X11L are expressed specifically in brain, while X11L2 is expressed ubiquitously. X11L is predominantly expressed in excitatory neurons, in contrast to X11, which is strongly expressed in inhibitory neurons. In vivo gene-knockout studies targeting X11, X11L, or both, and studies of X11 or X11L transgenic mice have reported that X11-family proteins suppress the amyloidogenic processing of endogenous mouse APP and ectopic human APP with one exception: knockout of X11, X11L or X11L2 has been found to suppress amyloidogenic metabolism in transgenic mice overexpressing the human Swedish mutant APP (APPswe) and the mutant human PS1, which lacks exon 9 (PS1dE9). Therefore, the data on X11-family protein function in transgenic human APP metabolism in vivo are inconsistent.Results: To confirm the interaction of X11L with human APP ectopically expressed in mouse brain, we examined the amyloidogenic metabolism of human APP in two lines of human APP transgenic mice generated to also lack X11L. In agreement with previous reports from our lab and others, we found that the amyloidogenic metabolism of human APP increased in the absence of X11L.Conclusion: X11L appears to aid in the suppression of amyloidogenic processing of human APP in brain in vivo, as has been demonstrated by previous studies using several human APP transgenic lines with various genetic backgrounds. X11L appears to regulate human APP in a manner similar to that seen in endogenous mouse APP metabolism.