Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation

Alzheimer's amyloid precursor protein (APP), the precursor of beta-amyloid (A beta), is an integral membrane protein with a receptor-like structure. W e recently demonstrated that the mature APP (mAPP; N- and O-glycosylated fo rm) is phosphorylated at Thr668 (numbering for APP695 isoform), specificall y in neurons. Phosphorylation of mAPP appears to occur during, and after, n euronal differentiation. Here we report that the phosphorylation of mAPP be gins 48-72 hr after treatment of PC12 cells with NGF and that this correlat es with the timing of neurite outgrowth. The phosphorylated form of APP is distributed in neurites and mostly in the growth cones of differentiating P C12 cells. PC12 cells stably expressing APP with Thr668Glu substitution sho wed remarkably reduced neurite extension after treatment with NGF. These ob servations suggest that the phosphorylated form of APP may play an importan t role in neurite outgrowth of differentiating neurons.