X11 INTERACTION WITH BETA-AMYLOID PRECURSOR PROTEIN MODULATES ITS CELLULAR STABILIZATION AND REDUCES AMYLOID BETA-PROTEIN SECRETION

The protein interaction domain of the neuronal protein X11 binds to th e YENPTY motif within the cytoplasmic domain of beta-amyloid precursor protein (beta APP). Amyloid-beta protein (A beta), the major constitu ent of the amyloid deposited in brain of Alzheimer's disease patients, is generated by proteolytic processing of beta APP, which occurs in p art following beta APP internalization. Because the YENPTY motif has a role in the internalization of beta APP, the effect of X11 binding on beta APP processing was studied in mouse neuroblastoma N2a, human emb ryonic kidney 293, monkey kidney COS-1, and human glial U251 cell line s transfected with wild type or mutated beta APP cDNAs. Secretion of s oluble beta APP via alpha-secretase activity increased significantly i n cells transfected with beta APP variants containing mutations that i mpair interaction with X11 when compared with cells transfected with w ild type cDNA Cotransfection of beta APP and X11 caused retention of c ellular beta APP, decreased secretion of s beta APP alpha, and decreas ed AP secretion. Thus, beta APP interaction with the protein interacti on domain of X11 stabilizes cellular beta APP and thereby participates in the regulation of beta APP processing pathways.