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γ-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease

机译：Aph1亚基中的γ-秘密酶异质性：与阿尔茨海默氏病的相关性

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摘要

The γ-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 γ-secretase complex in regulated intramembrane proteolysis of Notch and other essential proteins. Different γ-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 γ-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 γ-secretase activity in the human brain, and thus specific targeting of Aph1B-containing γ-secretase complexes may help generate less toxic therapies for Alzheimer's disease.
机译：γ-分泌酶复合物在阿尔茨海默氏病和癌症进展中起作用。然而，由于γ-分泌酶复合物在Notch和其他必需蛋白质的膜内蛋白水解的调控中的作用，使得临床上有用的抑制剂的开发变得复杂。包含不同早老素或Aph1蛋白亚基的不同γ-分泌酶复合物存在于各种组织中。在这里，我们显示这些复合物具有异质的生化和生理特性。小鼠阿尔茨海默氏病模型中Aph1Bγ-分泌酶的特异性失活导致与阿尔茨海默氏病相关的表型特征得到改善，而没有任何与Notch相关的副作用。 Aph1B复合物有助于人脑中的总γ-分泌酶活性，因此，特异性靶向含Aph1B的γ-分泌酶复合物可能有助于产生针对阿尔茨海默氏病的毒性较小的疗法。

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  • 来源
    《Science》 |2009年第5927期|639-642|共4页
  • 作者

    Lutgarde Serneels; Jerome Van Biervliet; Katleen Craessaerts; Tim Dejaegere; Katrien Horre; Tine Van Houtvin; Hermann Esselmann; Sabine Paul; Martin K. Schaefer; Oksana Berezovska; Bradley T. Hyman; Ben Sprangers; Raf Sciot; Lieve Moons; Mathias Jucker; Zhixiang Yang; Patrick C. May; Eric Karran; Jens Wiltfang; Rudi DHooge; Bart De Strooper;

  • 作者单位

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

    Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, 91054 Erlangen, Germany Department of Psychiatry and Psychotherapy, Rhine State Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany;

    Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, 91054 Erlangen, Germany Department of Psychiatry and Psychotherapy, Rhine State Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany;

    Department of Molecular Neurosciences, Institute of Anatomy and Cell Biology, Philipps University, D-35032 Marburg, Germany;

    Harvard Medical School Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disorders, Charlestown, MA 02129, USA;

    Harvard Medical School Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disorders, Charlestown, MA 02129, USA;

    Laboratory of Experimental Transplantation, KULeuven, 3000 Leuven, Belgium;

    Laboratory of Morphology and Molecular Pathology, KULeuven, 3000 Leuven, Belgium;

    Laboratory of Neural Circuit Development and Regeneration, Department of Biology, KULeuven, 3000 Leuven, Belgium;

    Department of Cellular Neurology, Hertie-lnstitute for Clinical Brain Research, University of Tubingen, D-72076 Tuebingen, Germany;

    Neuroscience Discovery Research, Lilly Research Labs, Eli Lilly and Co., Indianapolis, IN 46285, USA;

    Neuroscience Discovery Research, Lilly Research Labs, Eli Lilly and Co., Indianapolis, IN 46285, USA;

    Johnson and Johnson, Pharmaceutical Research and Development, 2340 Beerse, Belgium;

    Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, 91054 Erlangen, Germany Department of Psychiatry and Psychotherapy, Rhine State Hospital Essen, University of Duisburg-Essen, D-45147 Essen, Germany;

    Laboratory of Biological Psychology, Department of Psychology, KULeuven, 3000 Leuven, Belgium;

    Department for Molecular and Developmental Genetics, VIB, KULeuven, Herestraat 49, 3000 Leuven, Belgium Center for Human Genetics, KULeuven, Herestraat 49, 3000 Leuven, Belgium;

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  • 入库时间 2022-08-18 02:55:04

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