Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
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DOI：
10.1016/j.jbc.2021.100489
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Lauritzen I
中科院分区：
文献类型：
--
作者：
Checler F;Afram E;Pardossi-Piquard R;Lauritzen I
遗传学、生物化学和解剖学的基础导致了淀粉样蛋白级联假说的提出，该假说以淀粉样蛋白β肽（Aβ）的积累为中心来解释阿尔茨海默病（AD）的病因。在这种情况下，大量的努力旨在开发寻求降低Aβ水平的治疗策略，通过阻断其产生（γ-和β-分泌酶抑制剂）或通过中和其形成（Aβ定向免疫疗法）。然而，到目前为止，绝大多数（如果不是全部）基于这些策略的临床试验都失败了，因为它们无法恢复AD患者的认知功能，甚至在许多情况下，它们恶化了临床表现。我们在此提出，AD可能比简单的Aβ相关病理学更为复杂，并讨论了一种可能性，即一种将APP加工与AD联系起来的已证实遗传证据与基于Aβ的临床试验的一致失败相协调的方法，可以设想Aβ的直接前体，APP的β分泌酶衍生C末端片段βCTF（也称为C99）的病理学贡献。本文综述了C99是AD早期致病因子的证据，并认为γ-分泌酶不仅是一种产生Aβ的蛋白酶，而且是一种有益的C99失活酶。在这个意义上，我们讨论了靶向γ-分泌酶的分子的局限性，并提出了寻求通过其他手段降低C99水平的替代策略，特别是通过增强其溶酶体降解。
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.
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影响因子：
11.1
作者：
Acx H;Serneels L;Radaelli E;Muyldermans S;Vincke C;Pepermans E;Müller U;Chávez-Gutiérrez L;De Strooper B
通讯作者：
De Strooper B
影响因子：
7.8
作者：
Caccamo A;Magrì A;Medina DX;Wisely EV;López-Aranda MF;Silva AJ;Oddo S
通讯作者：
Oddo S
影响因子：
2.3
作者：
Calderon-Garciduenas, Ana Laura;Duyckaerts, Charles
通讯作者：
Duyckaerts, Charles
影响因子：
4.2
作者：
Bourgeois, Alexandre;Lauritzen, Inger;Pardossi-Piquard, Raphaelle
通讯作者：
Pardossi-Piquard, Raphaelle
DOI：
10.1124/jpet.112.199356
发表时间：
2013-03-01
影响因子：
3.5
作者：
Albright, Charles F.;Dockens, Randy C.;Tong, Gary
通讯作者：
Tong, Gary