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Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease

机译：γ-分泌酶激活蛋白是阿尔茨海默氏病的治疗靶标

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摘要

Accumulation of neurotoxic amyloid-β is a major hallmark of Alzheimer's disease. Formation of amyloid-β is catalysed by γ-secretase, a protease with numerous substrates. Little is known about the molecular mechanisms that confer substrate specificity on this potentially promiscuous enzyme. Knowledge of the mechanisms underlying its selectivity is critical for the development of clinically effective γ-secretase inhibitors that can reduce amyloid-β formation without impairing cleavage of other γ-secretase substrates, especially Notch, which is essential for normal biological functions. Here we report the discovery of a novel γ-secretase activating protein (GSAP) that drastically and selectively increases amyloid-β production through a mechanism involving its interactions with both γ-secretase and its substrate, the amyloid precursor protein carboxy-terminal fragment (APP-CTF). GSAP does not interact with Notch, nor does it affect its cleavage. Recombinant GSAP stimulates amyloid-β production in vitro. Reducing GSAP concentrations in cell lines decreases amyloid-β concentrations. Knockdown of GSAP in a mouse model of Alzheimer's disease reduces levels of amyloid-β and plaque development. GSAP represents a type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anticancer drug previously found to inhibit amyloid-β formation without affecting Notch cleavage, achieves its amyloid-β-lowering effect by preventing GSAP interaction with the γ-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-β-lowering therapeutic target without affecting other key functions of γ-secretase.
机译：神经毒性淀粉样β蛋白的积累是阿尔茨海默氏病的主要标志。 γ-分泌酶是一种具有多种底物的蛋白酶，可催化淀粉样β蛋白的形成。对于这种潜在混杂的酶赋予底物特异性的分子机制了解甚少。了解其选择性的基本机制对于开发临床有效的γ-分泌酶抑制剂至关重要，该抑制剂可减少淀粉样β的形成而不会损害其他γ-分泌酶底物的裂解，尤其是Notch，这对于正常的生物学功能至关重要。在这里我们报道了一种新型的γ-分泌酶激活蛋白（GSAP）的发现，该蛋白通过一种涉及与γ-分泌酶及其底物，淀粉样前体蛋白羧基末端片段（APP）相互作用的机制来显着选择性地增加淀粉样β的产生-CTF）。 GSAP不会与Notch相互作用，也不会影响其裂解。重组GSAP在体外刺激淀粉样β的产生。降低细胞系中的GSAP浓度会降低淀粉样β浓度。阿尔茨海默氏病小鼠模型中的GSAP抑制可降低β-淀粉样蛋白水平和斑块形成。 GSAP代表一种γ分泌酶调节剂，它通过与特定底物相互作用来指导酶的特异性。我们证明伊马替尼是一种先前发现可抑制淀粉样β形成而又不影响Notch裂解的抗癌药物，它通过阻止GSAP与γ-分泌酶底物APP-CTF相互作用来达到降低淀粉样β的作用。因此，GSAP可以作为降低淀粉样β的治疗靶标，而不会影响γ分泌酶的其他关键功能。

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  • 来源
    《Nature》 |2010年第7311期|P.95-98|共4页
  • 作者

    Gen He; Wenjie Luo; Peng Li; Christine Remmers; William J. Netzer; Joseph Hendrick; Karima Bettayeb; Marc Flajolet; Fred Gorelick; Lawrence P. Wennogle; Paul Greengard;

  • 作者单位

    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnlntra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnlntra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

    rnDepartment of Internal Medicine and Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA VA Connecticut Healthcare, 333 Cedar Street, New Haven, Connecticut 06520, USA;

    rnlntra-Cellular Therapies, Inc., Audubon Biomedical Science and Technology Park, 3960 Broadway, New York, New York 10032, USA;

    rnLaboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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