Bukhari Hassan, Glotzbach Annika, Kolbe Katharina, Leonhardt Gregor, Loosse Christina, Müller Thorsten
Department of Molecular Biochemistry, Faculty of Chemistry and Biochemistry, Ruhr University Bochum, Universitätsstr. 150, 44780, Bochum, Germany; Cell Signaling in Neurodegeneration, Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
Cell Signaling in Neurodegeneration, Medical Proteome-Center, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany.
Prog Neurobiol. 2017 Sep;156:189-213. doi: 10.1016/j.pneurobio.2017.05.005. Epub 2017 Jun 3.
Alzheimer's disease (AD) is the most common neurodegenerative disease with tens of millions of people affected worldwide. The pathogenesis is still poorly understood and various therapeutical approaches targeting the amyloid β (Aβ) peptide, a product of the amyloidogenic cleavage of the amyloid precursor protein (APP), failed. Moreover, a couple of studies critically questioned the relevance of Aβ in the pathogenesis of AD. Thus, new ideas need to be studied and one highly interesting hypothesis is the APP mediated signal transduction to the nucleus. As a consequence nuclear -potentially toxic- structures emerge, which were recently found to a high extent in human AD tissue and thus, may contribute to neurodegeneration. Relevant for the signaling machinery are modifications at the very C-terminal end of the precursor protein, the APP intracellular domain (AICD). In this review we update the knowledge on mechanisms on AICD referring to our 2008 article: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-Relevance for Alzheimer's disease (T. Muller, et al., 2008). We summarize how AICD is generated and degraded, we describe its intramolecular motifs, translational modifications, and how those as well as APP dimerization influence AICD generation and function. Moreover, we resume the AICD interactome and elucidate AICDs involvement in nuclear signaling, transcriptional regulation, cell death, DNA repair and cell cycle re-entry and we give insights in its physiological function. Results are summarized in the comprehensive poster "The world of AICD".
阿尔茨海默病（AD）是最常见的神经退行性疾病，全球数千万人受其影响。其发病机制仍知之甚少，针对淀粉样前体蛋白（APP）淀粉样生成性切割产物淀粉样β（Aβ）肽的各种治疗方法均告失败。此外，一些研究对Aβ在AD发病机制中的相关性提出了严重质疑。因此，需要研究新的思路，一个非常有趣的假说是APP介导的信号转导至细胞核。结果出现了潜在有毒的核结构，最近在人类AD组织中大量发现，因此可能导致神经退行性变。与信号传导机制相关的是前体蛋白即APP细胞内结构域（AICD）最末端的修饰。在本综述中，我们参考2008年发表的文章：淀粉样前体蛋白细胞内结构域（AICD）作为基因表达、细胞凋亡和细胞骨架动力学的调节剂——与阿尔茨海默病的相关性（T. 穆勒等人，2008年），更新关于AICD机制的知识。我们总结了AICD是如何产生和降解的，描述了其分子内基序、翻译后修饰，以及这些修饰和APP二聚化如何影响AICD的产生和功能。此外，我们回顾了AICD相互作用组，阐明了AICD在核信号传导、转录调控、细胞死亡、DNA修复和细胞周期重新进入中的作用，并深入探讨了其生理功能。结果总结在综合海报《AICD的世界》中。
