Serneels Lutgarde, Van Biervliet Jérôme, Craessaerts Katleen, Dejaegere Tim, Horré Katrien, Van Houtvin Tine, Esselmann Hermann, Paul Sabine, Schäfer Martin K, Berezovska Oksana, Hyman Bradley T, Sprangers Ben, Sciot Raf, Moons Lieve, Jucker Mathias, Yang Zhixiang, May Patrick C, Karran Eric, Wiltfang Jens, D'Hooge Rudi, De Strooper Bart
Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium.
Science. 2009 May 1;324(5927):639-42. doi: 10.1126/science.1171176. Epub 2009 Mar 19.
The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. The development of clinically useful inhibitors, however, is complicated by the role of the gamma-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different gamma-secretase complexes containing different Presenilin or Aph1 protein subunits are present in various tissues. Here we show that these complexes have heterogeneous biochemical and physiological properties. Specific inactivation of the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to improvements of Alzheimer's disease-relevant phenotypic features without any Notch-related side effects. The Aph1B complex contributes to total gamma-secretase activity in the human brain, and thus specific targeting of Aph1B-containing gamma-secretase complexes may help generate less toxic therapies for Alzheimer's disease.
γ-分泌酶复合物在阿尔茨海默病和癌症进展中起作用。然而，由于γ-分泌酶复合物在Notch及其他重要蛋白质的调节性膜内蛋白水解中所起的作用，临床上有用的抑制剂的开发变得复杂。不同组织中存在含有不同早老素或Aph1蛋白亚基的不同γ-分泌酶复合物。在这里，我们表明这些复合物具有异质的生化和生理特性。在小鼠阿尔茨海默病模型中特异性失活Aph1Bγ-分泌酶可改善与阿尔茨海默病相关的表型特征，且无任何与Notch相关的副作用。Aph1B复合物对人脑中总的γ-分泌酶活性有贡献，因此特异性靶向含Aph1B的γ-分泌酶复合物可能有助于开发毒性较小的阿尔茨海默病治疗方法。
