The AICD fragment of APP initiates a FoxO3a mediated response via FANCD2

Abstract

The amyloid precursor protein (APP) is a cell surface protein of uncertain function that is notable for being the parent protein of beta-amyloid. Research around this protein has focussed heavily on the link to Alzheimer's disease and neurodegeneration. However, there is increasing evidence that APP may be linked to neuronal loss through mechanisms independent of beta-amyloid. FoxO3a is a transcription factor associated with neuronal longevity and apoptosis. In neurons, FoxO3a is associated with cell death through pathways that include BIM, a BCL-2 family member. In this study we have shown that APP overexpression increased the cellular levels and activity of FoxO3a. This increased expression and activity is not a result of decreased phosphorylation but is more likely a result of increased nuclear stability due to increased levels of FANCD2, a binding partner of FoxO3a. The changes caused by APP overexpression were shown to be due to the AICD fragment of APP possibly directly inducing transcription increase in FANCD2. These findings strengthen the link between APP metabolism and FoxO3a neuronal activity. This link may be crucial in better understanding the cellular role of APP and its link to neurodegeneration and aging.

Keywords: Amyloid; BIM; FANCD2; FoxO3a; Neurodegeneration.