X11 Proteins Regulate the Translocation of Amyloid β-Protein Precursor (APP) into Detergent-resistant Membrane and Suppress the Amyloidogenic Cleavage of APP by β-Site-cleaving Enzyme in Brain
X11 Proteins Regulate the Translocation of Amyloid β-Protein Precursor (APP) into Detergent-resistant Membrane and Suppress the Amyloidogenic Cleavage of APP by β-Site-cleaving Enzyme in Brain
复制标题
DOI：
10.1074/jbc.m801353200
复制
发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Suzuki, Toshiharu
中科院分区：
文献类型：
--
作者：
Saito, Yuhki;Sano, Yoshitake;Suzuki, Toshiharu
X11和X11样蛋白（X11 L）是神经元衔接蛋白，其与淀粉样β蛋白前体（APP）的胞质结构域的结合抑制与阿尔茨海默病发病机制有关的淀粉样β蛋白（A β）的产生。在缺乏X11 L的突变小鼠的脑中，APP的淀粉样蛋白生成代谢而非淀粉样蛋白分解代谢选择性增加（佐野，Y.，Syuzo-Takabatake，A.，Nakaya，T.，Saito，Y.，富田，S.，Itohara，S.，和Suzuki，T.（2006）J.Biol.Chem.281，37853-37860）。为了揭示X11蛋白（X11 s）在体内抑制APP的淀粉样蛋白裂解中的实际作用，我们制备了X11和X11 L双基因敲除小鼠，并分析了APP的代谢。突变小鼠显示APP的β位点裂解增强沿着脑中A β的积累增加，APP与β位点APP裂解酶（BACE）的共定位增加。在同时缺乏X11和X11 L的小鼠脑中，成熟APP及其β-C-末端片段的表观相对亚细胞分布向耐洗涤剂膜（DRM）部分转移，DRM是一种细胞器，其中BACE是活性的，几乎没有发现两个X11。这些结果表明，X11主要与DRM之外的APP分子相关，APP-X11/X11 L复合物的解离导致APP进入DRM，并且DRM内BACE对未复合APP的切割通过X11 s缺陷而增强。目前的结果导致一种想法，即X11 L在与APP相互作用中的功能障碍可能会招募更多的APP进入DRM并增加A β的产生，即使脑中BACE活性没有增加。
X11 and X11-like proteins (X11L) are neuronal adaptor proteins whose association to the cytoplasmic domain of amyloid beta-protein precursor (APP) suppresses the generation of amyloid beta-protein (A beta) implicated in Alzheimer disease pathogenesis. The amyloidogenic, but not amyloidolytic, metabolism of APP was selectively increased in the brain of mutant mice lacking X11L (Sano, Y., Syuzo-Takabatake, A., Nakaya, T., Saito, Y., Tomita, S., Itohara, S., and Suzuki, T. (2006) J. Biol. Chem. 281, 37853-37860). To reveal the actual role of X11 proteins (X11s) in suppressing amyloidogenic cleavage of APP in vivo, we generated X11 and X11L double knock-out mice and analyzed the metabolism of APP. The mutant mice showed enhanced beta-site cleavage of APP along with increased accumulation of A beta in brain and increased colocalization of APP with beta-site APP-cleaving enzyme (BACE). In the brains of mice deficient in both X11 and X11L, the apparent relative subcellular distributions of both mature APP and its beta-C-terminal fragment were shifted toward the detergent-resistant membrane (DRM) fraction, an organelle in which BACE is active and both X11s are not nearly found. These results indicate that X11s associate primarily with APP molecules that are outside of DRM, that the dissociation of APP-X11/X11L complexes leads to entry of APP into DRM, and that cleavage of uncomplexed APP by BACE within DRM is enhanced by X11s deficiency. Present results lead to an idea that the dysfunction of X11L in the interaction with APP may recruit more APP into DRM and increase the generation of A beta even if BACE activity did not increase in brain.