Journal of Alzheimers Disease & Parkinsonism
Open Access

Abstract

The amyloid precursor protein (APP) is a broadly expressed transmembrane protein that plays 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 ? (A?) peptides and APP intracellular domain (AICD). While A? 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 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 FoxOinduced transcription of pro-apoptotic gene Bim. These data demonstrate that APP modulates FoxO-mediated cell death and locomotion defect through AICD, which acts as a transcriptional co-activator of FoxO.Our studysheds light on the potential therapeutic target of Alzheimer?s disease.

Biography