FoxO mediates APP-induced AICD-dependent cell death

作者：Wang X; Wang Z; Chen Y; Huang X; Hu Y; Zhang R; Ho M S; Xue L^*

来源：Cell Death & Disease, 2014, 5(5): e1233.

DOI：10.1038/cddis.2014.196

The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that has a significant role in the pathogenesis of Alzheimer's disease (AD). APP can be cleaved at multiple sites to generate a series of fragments including the amyloid beta (A beta) peptides and APP intracellular domain (AICD). Although A beta peptides have been proposed to be the main cause of AD pathogenesis, the role of AICD has been underappreciated. Here we report that APP induces AICD-dependent cell death in Drosophila neuronal and non-neuronal tissues. Our genetic screen identified the transcription factor forkhead box O (FoxO) as a crucial downstream mediator of APP-induced cell death and locomotion defect. In mammalian cells, AICD physically interacts with FoxO in the cytoplasm, translocates with FoxO into the nucleus upon oxidative stress, and promotes FoxO-induced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death through AICD, which acts as a transcriptional co-activator of FoxO.

• 出版日期2014-5
• 单位同济大学