X11 interaction with β-amyloid precursor protein modulates its cellular stabilization and reduces amyloid β-protein secretion

The protein interaction domain of the neuronal protein X11 binds to the YENPTY motif within the cytoplasmic domain of beta-amyloid precursor protein (beta APP). Amyloid-beta protein (A beta), the major constituent of the amyloid deposited in brain of Alzheimer's disease patients, is generated by proteolytic processing of beta APP, which occurs in part 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 embryonic kidney 293, monkey kidney COS-1, and human glial U251 cell lines transfected with wild type or mutated beta APP cDNAs. Secretion of soluble beta APP via alpha-secretase activity increased significantly in cells transfected with beta APP variants containing mutations that impair interaction with X11 when compared with cells transfected with wild type cDNA Cotransfection of beta APP and X11 caused retention of cellular beta APP, decreased secretion of s beta APP alpha, and decreased AP secretion. Thus, beta APP interaction with the protein interaction domain of X11 stabilizes cellular beta APP and thereby participates in the regulation of beta APP processing pathways.