DZNE - German Center for Neurodegenerative Diseases, 80336 Munich, Germany.
Curr Alzheimer Res. 2012 Feb;9(2):165-77. doi: 10.2174/156720512799361655.
α-secretase is the name for a metalloprotease activity, which is assumed to play a key role in the prevention of the molecular mechanisms underlying Alzheimer's disease (AD). Proteases similar to α-secretase are essential for a wide range of biological processes, such as cell adhesion and embryonic development. The molecular culprit in AD is the amyloid β peptide (Aβ), which derives from the amyloid precursor protein (APP) through sequential cleavage by the two proteases β- and γ-secretase. In contrast, α-secretase, which is the metalloprotease ADAM10, cleaves APP within the Aβ domain, thus preventing Aβ generation. Additionally, it produces a secreted APP ectodomain with neurotrophic and neuroprotective properties. An increase in α-secretase cleavage is considered a therapeutic approach for AD, but the molecular mechanisms regulating α-secretase cleavage are only partly known. Protein kinase C and mitogen-activated protein kinase constitute central signaling hubs for the regulation of α-secretase cleavage. Additionally, recent studies increasingly demonstrate that the correct spatial and temporal localization of the two membrane proteins APP and α-secretase is essential for efficient α-secretase cleavage of APP. This review highlights the role of signaling pathways and protein trafficking in the control of APP α-secretase cleavage.
α-分泌酶是一种金属蛋白酶活性的名称，据推测它在预防阿尔茨海默病（AD）的分子机制中发挥关键作用。与 α-分泌酶类似的蛋白酶对于广泛的生物过程至关重要，例如细胞粘附和胚胎发育。AD 中的分子罪魁祸首是淀粉样 β 肽（Aβ），它通过β-和γ-分泌酶的两种蛋白酶的顺序切割从淀粉样前体蛋白（APP）中衍生而来。相比之下，α-分泌酶（ADAM10 是一种金属蛋白酶）在 Aβ 结构域内切割 APP，从而防止 Aβ 的产生。此外，它还产生具有神经营养和神经保护特性的分泌型 APP 细胞外结构域。增加 α-分泌酶的切割被认为是 AD 的一种治疗方法，但调节 α-分泌酶切割的分子机制仅部分已知。蛋白激酶 C 和丝裂原活化蛋白激酶构成了调节 α-分泌酶切割的核心信号枢纽。此外，最近的研究越来越多地表明，两种膜蛋白 APP 和 α-分泌酶的正确空间和时间定位对于 APP 的有效 α-分泌酶切割至关重要。这篇综述强调了信号通路和蛋白质运输在控制 APP α-分泌酶切割中的作用。
