Department of Psychiatry Research, University Zurich, Zurich.
Curr Alzheimer Res. 2012 Feb;9(2):200-16. doi: 10.2174/156720512799361673.
Altered proteolytic processing of the β-amyloid precursor protein (APP) is a central event in familial and sporadic Alzheimer's disease (AD). In a process termed regulated intramembrane proteolysis (RIP), APP first undergoes ectodomain shedding executed either by α- secretases at the plasma membrane or by β-secretase in the endosomal compartment. The remaining membrane-anchored stubs are cleaved within the membrane plane by the γ-secretase complex, releasing the APP intracellular domain (AICD) into the cytosol and leading to the generation of the Aβ peptide in the amyloidogenic pathway that is initiated by β-secretase. The Aβ peptides aggregate to form soluble oligomers and finally deposit into amyloid plaques that are a hallmark of AD. Recent evidence indicates a role for Aβ oligomers in regulating synaptic plasticity with excess amounts of oligomers disrupting synaptic function. The amyloid cascade hypothesis of AD is centered on the Aβ peptide, the APP fragment that has been most intensely studied, while other cleavage products have been largely neglected. The secreted ectodomain generated after α-cleavage in the non-amyloidogenic pathway has neurotrophic and neuroproliferative activities, thus opposing the neurotoxicity observed with high concentrations of Aβ. Further, in analogy to many other membrane proteins that are subject to RIP, AICD can translocate to the nucleus to regulate transcription. Many RIP substrates are localized to the synapse and thus could convey a direct signal from the synapse to the nucleus upon cleavage. Evidence indicates that only the amyloidogenic pathway generates AICD capable of nuclear signaling, due to the subcellular compartmentalization of APP processing. In aging and sporadic AD there is an increase in β-secretase levels and activity generating more Aβ peptides and concomitantly leading to an increase in AICD nuclear signaling. In this review, I summarize the current knowledge on AICD nuclear signaling and propose mechanisms to explain how this physiological function of APP might impact the pathology seen in AD.
β-淀粉样前体蛋白（APP）的蛋白水解加工改变是家族性和散发性阿尔茨海默病（AD）的核心事件。在一个称为调节膜内蛋白水解（RIP）的过程中，APP 首先经历由质膜上的α-分泌酶或内体隔室中的β-分泌酶执行的外显肽脱落。剩余的膜锚定残基在膜平面内被 γ-分泌酶复合物切割，将 APP 细胞内结构域（AICD）释放到细胞质中，并导致在β-分泌酶起始的淀粉样蛋白途径中产生 Aβ肽。Aβ肽聚集形成可溶性寡聚物，最终沉积到淀粉样斑块中，这是 AD 的标志。最近的证据表明 Aβ寡聚物在调节突触可塑性中起作用，过量的寡聚物会破坏突触功能。AD 的淀粉样蛋白级联假说以 Aβ肽为中心，这是研究最多的 APP 片段，而其他裂解产物在很大程度上被忽视了。在非淀粉样蛋白途径中经α-切割产生的分泌型外显肽具有神经营养和神经增殖活性，因此与高浓度 Aβ观察到的神经毒性相反。此外，与许多其他受 RIP 影响的膜蛋白类似，AICD 可以易位到细胞核中调节转录。许多 RIP 底物定位于突触，因此在切割后可以将来自突触的直接信号传递到细胞核。有证据表明，只有淀粉样蛋白途径产生能够进行核信号传递的 AICD，这是由于 APP 加工的亚细胞区室化。在衰老和散发性 AD 中，β-分泌酶水平和活性增加，产生更多的 Aβ肽，同时导致 AICD 核信号传递增加。在这篇综述中，我总结了关于 AICD 核信号传递的最新知识，并提出了一些机制来解释 APP 的这种生理功能如何影响 AD 中看到的病理学。
