Proteolytic processing of Alzheimer's β-amyloid precursor protein.
Proteolytic processing of Alzheimer's β-amyloid precursor protein.
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DOI：
10.1111/j.1471-4159.2011.07519.x
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发表时间：
2012-01
影响因子：
4.7
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Zhang H;Ma Q;Zhang YW;Xu H
β-淀粉样前体蛋白（APP）是阿尔茨海默病（AD）发病机制中的关键因子。APP经过翻译后蛋白水解/加工产生疏水性β-淀粉样蛋白（Aβ）肽。Aβ在脑中沉积，形成寡聚Aβ和斑块，被确定为AD的关键病理学标志之一。APP生成Aβ的过程由β-和γ-分泌酶执行，并受到高度调节。在体外和体内AD模型中，Aβ毒性可导致突触功能障碍、神经元细胞死亡、学习/记忆受损和行为异常。除Aβ外，APP的蛋白水解裂解也可产生APP胞内结构域（AICD），据报道其参与多种类型的细胞事件，如基因转录和凋亡性细胞死亡。除了淀粉样蛋白加工外，APP还可以被α-分泌酶切割，形成可溶性或分泌性APP胞外域（sAPP-α），其已被证明主要具有神经保护作用。本文综述了APP代谢的机制及其各种蛋白水解产物的可能功能，以期更好地了解APP的病理生理功能。
β–amyloid precursor protein (APP) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). APP undergoes posttranslational proteolysis/processing to generate the hydrophobic β-amyloid (Aβ) peptides. Deposition of Aβ in the brain, forming oligomeric Aβ and plaques, is identified as one of the key pathological hallmarks of AD. The processing of APP to generate Aβ is executed by β- and γ-secretase and is highly regulated. Aβ toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo. Aside from Aβ, proteolytic cleavages of APP can also give rise to the APP intracellular domain (AICD), reportedly involved in multiple types of cellular events such as gene transcription and apoptotic cell death. In addition to amyloidogenic processing, APP can also be cleaved by α-secretase to form a soluble or secreted APP ectodomain (sAPP-α) that has been shown to be mostly neuro-protective. In this review, we describe the mechanisms involved in APP metabolism and the likely functions of its various proteolytic products to give a better understanding of the patho/physiological functions of APP.
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