Expression of mDab1 promotes the stability and processing of amyloid precursor protein and this effect is counteracted by X11α

The cytoplasmic tail of amyloid precursor protein (APP) possesses the NPTY motif to which several phosphotyrosine-binding domain-containing proteins bind, including X11α and mDab1. X11α has been shown to slow cellular APP processing and reduce secretion of Aβ peptides. However, the effect of mDab1 on APP processing has not been determined. Here, we show that mDab1 increases the levels of cellular mature APP and promotes its processing by the secretases in both transiently transfected HEK 293 cells and in neuroglioma U251 cells. These effects derive specifically from the interaction of APP with mDab1 since they are not observed in APP deletion mutants lacking the interaction module NPTY. We further demonstrate that mDab1 enhances cell surface expression of APP, possibly by interfering with its endocytosis. Interestingly, X11α and mDab1 exert opposing effects on APP processing. However, when both proteins are co-expressed the effect of X11α overrides that of mDab1. Taken together, these results suggest that the relative stoichiometry and binding affinity of the adaptor proteins determines the final outcome on APP metabolism.