Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer's disease.
Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer's disease.
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DOI：
10.1016/j.biopsych.2014.06.003
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发表时间：
2015-04-15
影响因子：
10.6
通讯作者：
Pratico, Domenico
中科院分区：
文献类型：
--
作者：
Chu, Jin;Li, Jian-Guo;Joshi, Yash B.;Giannopoulos, Phillip F.;Hoffman, Nicholas E.;Madesh, Muniswamy;Pratico, Domenico
关键词：
阿尔茨海默病（AD）的一个主要特征是β淀粉样蛋白（Aβ）的积累，其形成受γ-分泌酶复合物及其激活蛋白（也称为GSAP）的调节。由于GSAP与γ-分泌酶相互作用而不影响Notch的切割，因此它是抗β治疗的理想靶点。然而，尽管人们对这种蛋白质很感兴趣，但其神经生物学机制尚不清楚。利用AD患者死后脑组织、AD转基因小鼠模型和神经元细胞研究GSAP形成和淀粉样蛋白形成的分子机制。我们在GSAP序列中发现了一个caspase-3加工结构域，并提供了实验证据，证明该caspase对GSAP的激活和a β肽的生物发生至关重要。此外，我们证明caspase-3依赖性GSAP的形成发生在AD个体和两种不同AD小鼠模型的大脑中，并且该过程具有生物学相关性，因为其药物阻断可减少体内Aβ病理。通过鉴定caspase-3是GSAP和a β产生的内源性调节剂，我们的数据表明它是一种新的、有吸引力的、可行的降低AD的a β治疗靶点。
A major hallmark feature of Alzheimer’s disease (AD) is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with the γ-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are not known. Post-mortem brain tissues from AD patients, transgenic mouse models of AD and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis. We identify a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrate that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD, and that the process is biologically relevant since its pharmacological blockade reduces Aβ pathology in vivo. Our data by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production establish it as a novel, attractive and viable Aβ lowering therapeutic target for AD.
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