The neuronal adaptor X11α interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Aβ40 and Aβ42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11α-mediated effects on APP trafficking and metabolism, and that X11α modulates APP metabolism in both secretory and endocytic pathways. X11α failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. However, endocytic-competent APPswe Y743A had unique trafficking and metabolism including a prolonged half-life and increased secretion of catabolites compared with APPswe. In contrast to endocytic-defective mutants, X11α interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11α with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Aβ40, and Aβ42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11α modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Aβ generated in either pathway.
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