The X11α protein slows cellular amyloid precursor protein processing and reduces Aβ40 and Aβ42 secretion

Constitutive amyloid precursor protein (APP) metabolism results in the generation of soluble APP (APPs) and A beta peptides, including A beta 40 and A beta 42-the major component of amyloid plaques in Alzheimer's disease brain. The phosphotyrosine binding (PTB) domain of X11 binds to a peptide containing a YENPTY motif found in the carboxyl terminus of APP. We have cloned the full-length X11 gene now referred to as X11 alpha. Coexpression of X11 alpha with APP results in comparatively greater levels of cellular APP and less APPs, A beta 40, and A beta 42 recovered in conditioned medium of transiently transfected HEK 293 cells. These effects are impaired by a single missense mutation of either APP (Y682G within the YENPTY motif) or X11 alpha (F608V within the PTB domain), which diminishes their interaction, thus demonstrating specificity. The inhibitory effect of X11 alpha on A beta 40 and A beta 42 secretion is amplified by coexpression with the Swedish mutation of APP (K595N/M596L), which promotes its amyloidogenic processing. Pulse-chase analysis demonstrates that X11 alpha prolongs the half-life of APP from similar to 2 h to similar to 4 h. The effects of X11 alpha on cellular APP and APPs recovery were confirmed in a 293 cell line stably transfected with APP. The specific binding of the PTB domain of X11 alpha to the YENPTY motif-containing peptide of APP appears to slow cellular APP processing and thus reduces recovery of its soluble fragments APPs, A beta 40, and A beta 42 in conditioned medium of transfected HEK 293 cells, X11 alpha may be involved in APP trafficking and metabolism in neurons and thus may be implicated in amyloidogenesis in normal aging and Alzheimer's disease brain.