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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
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Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

机译：γ-分泌酶是有毒的App C-末端片段C99的有益灭活酶吗？

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Genetic, biochemical, and anatomical grounds led to the proposal of the amyloid cascade hypothesis centered on the accumulation of amyloid beta peptides (Aβ) to explain Alzheimer's disease (AD) etiology. In this context, a bulk of efforts have aimed at developing therapeutic strategies seeking to reduce Aβ levels, either by blocking its production (γ- and β-secretase inhibitors) or by neutralizing it once formed (Aβ-directed immunotherapies). However, so far the vast majority of, if not all, clinical trials based on these strategies have failed, since they have not been able to restore cognitive function in AD patients, and even in many cases, they have worsened the clinical picture. We here propose that AD could be more complex than a simple Aβ-linked pathology and discuss the possibility that a way to reconcile undoubted genetic evidences linking processing of APP to AD and a consistent failure of Aβ-based clinical trials could be to envision the pathological contribution of the direct precursor of Aβ, the β-secretase-derived C-terminal fragment of APP, βCTF, also referred to as C99. In this review, we summarize scientific evidences pointing to C99 as an early contributor to AD and postulate that γ-secretase should be considered as not only an Aβ-generating protease, but also a beneficial C99-inactivating enzyme. In that sense, we discuss the limitations of molecules targeting γ-secretase and propose alternative strategies seeking to reduce C99 levels by other means and notably by enhancing its lysosomal degradation.
机译：遗传，生化和解剖学接地导致了淀粉样级级联假设的提议，以淀粉样蛋白β肽（Aβ）积累，解释Alzheimer疾病（AD）病因。在这种情况下，大部分努力旨在通过阻断其生产（γ-和β-分泌酶抑制剂）或通过形成（Aβ-指导的免疫疗法）来制定寻求降低Aβ水平的治疗策略。然而，到目前为止，如果不是全部，基于这些策略的临床试验已经失败了，因为他们没有能够恢复广告患者的认知功能，甚至在许多情况下，它们已经恶化了临床图。我们在此提出广告可能比简单的Aβ联系病理更复杂，并讨论可令人难以置信的遗传证据的方法，这些方法可以将应用程序的加工联系到广告和β基临床试验的一致失败可能是为了设想病理学Aβ直接前体的贡献，APP，βCTF的β-分泌酶衍生的C末端片段，也称为C99。在本文中，我们总结了指向C99的科学证据，作为广告的早期贡献者，假设γ-分泌酶应该被认为不仅是Aβ-产生的蛋白酶，而且是一种有益的C99灭活酶。从这种意义上讲，我们讨论了靶向γ-分泌酶的分子的局限性，并提出寻求通过其他方式的替代策略通过其他方式减少C99水平，值得注意的是提高其溶酶体降解。

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