Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease.
Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease.
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神经毒性β淀粉样蛋白(Aβ)的蓄积是阿尔茨海默病(AD)的主要标志。Aβ的形成是由γ分泌酶催化的，这是一种具有多种底物的蛋白酶。对这种潜在的杂交酶赋予底物专一性的分子机制知之甚少。了解其选择性的机制对于开发临床上有效的γ分泌酶抑制剂至关重要，它可以减少Aβ的形成，而不损害其他γ分泌酶底物的切割，特别是对正常生物学功能至关重要的Notch。在这里，我们发现了一种新的γ分泌酶激活蛋白(GSAP)，它通过与β分泌酶及其底物淀粉样前体蛋白C末端片段(APP-CTF)相互作用的机制，显著和选择性地增加Aγ的产生。GSAP不与Notch相互作用，也不影响其切割。重组gSAP在体外刺激Aβ的产生降低细胞系中GSAP水平会降低Aβ水平。在阿尔茨海默病小鼠模型中敲除GSAP可以降低Aβ水平和斑块形成。GSAP代表了一种新型的γ分泌酶调节因子，它通过与特定底物相互作用来指导酶的特异性。我们证明了伊马替尼是一种抗癌药物，可以在不影响β切割的情况下抑制Aβ的形成，它是通过阻止GSAP与γ分泌酶底物APP-CTF的相互作用而实现的。因此，GSAP可以作为一个降低β的治疗靶点，而不影响γ-分泌酶的其他关键功能。
Accumulation of neurotoxic βamyloid (Aβ) is a major hallmark of Alzheimer's disease (AD). Formation of Aβ is catalyzed by γsecretase, 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 Aβ 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), which dramatically and selectively increases Aβ production through a mechanism involving its interactions with both γsecretase and its substrate, the amyloid precursor protein C-terminal fragment (APP-CTF). gSAP does not interact with Notch nor does it affect its cleavage. Recombinant gSAP stimulates Aβ production in vitro. Reducing gSAP levels in cell lines decreases Aβ levels. Knockdown of gSAP in a mouse model of Alzheimers disease reduces levels of Aβ and plaque development. gSAP represents a new type of γ-secretase regulator that directs enzyme specificity by interacting with a specific substrate. We demonstrate that imatinib, an anti-cancer drug previously found to inhibit Aβ formation without affecting Notch cleavage, achieves its Aβ-lowering effect by preventing gSAP interaction with the γ-secretase substrate, APP-CTF. Thus, gSAP can serve as an Aβ-lowering therapeutic target without affecting other key functions of γ-secretase.
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