Gastrokine 1 (GKN1) is highly expressed in gastric tissue and is secreted into the stomach but is not expressed in gastric cancer. GKN1 belongs to the BRICHOS domain family and plays a major role in maintaining gastric mucosa integrity. We previously demonstrated that a recombinant human GKN1 protein was able to interact with the amyloid precursor protein (APP) and was endowed with an antiamyloidogenic property because it inhibited polymerization of the A beta(1-40) peptide released from APP upon its partial hydrolysis. Here, we report that GKN1 can act as a physiological suppressor of A beta production in gastric cancer cells. GKN1 blocked the access of gamma-secretase to APP, thereby facilitating the cleavage of APP by alpha- and beta-secretases. GKN1 directly interacted with APP C-terminal fragments, C83 and C99. In addition, it did not affect gamma-secretase activity in gastric cancer cells because it did not alter Notchl processing. GKN1-mediated inhibition of APP processing might represent a new approach for the prevention and therapy of Alzheimer's disease (AD). (C) 2017 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.