X11a impairs c- but not b-cleavage of amyloid precursor protein

The phosphotyrosine binding domain of the neuronal protein X11a/mint-1 binds to the C-terminus of amyloid precursor protein (APP) and inhibits catabolism to b-amyloid (Ab), but the mechanism of this effect is unclear. Coexpression of X11a or its PTB domain with APPswe inhibited secretion of Ab40 but not APPsbswe, suggesting inhibition of cbut not b-secretase. To further probe cleavage(s) inhibited by X11a, we coexpressed b-secretase (BACE-1) or a component of the c-secretase complex (PS-1D9) with APP, APPswe, or C99, with and without X11a, in HEK293 cells. X11a suppressed the PS-1D9-induced increase in Ab42 secretion generated from APPswe or C99. However, X11a did not impair BACE-1-mediated proteolysis of APP or APPswe to C99. In contrast to impaired c-cleavage of APPswe, X11a or its PTB domain did not inhibit c-cleavage of NotchDE to NICD (the Notch intracellular domain). The X11a PDZ–PS.1D9 interaction did not affect c-cleavage activity. In a cell-free system, X11a did not inhibit the catabolism of APP C-terminal fragments. These data suggest that X11a may inhibit Ab secretion from APP by impairing its trafficking to sites of active c-secretase complexes. By specifically targeting substrate instead of enzyme X11a may function as a relatively specific c-secretase inhibitor.