Abnormal Proteolytic processing of amyloid precursor protein (APP) is a pathologic feature of Alzheimer's disease. Recent studies have demonstrated that serine/threonine phosphorylation specifically at amino-acid residue Thr668 (APP695 numbering) regulates APP processing. In this study, we investigated the possibility that tyrosine phosphorylation of APP regulates APP Processing. A tyrosine kinase inhibitor decreased expression of the C83 fragment which is a cleaved product of APP by alpha-secretase. By overexpressing APP mutant proteins, Tyr687 was found to be the major tyrosine kinase phosphorylation site. Expression of the C83 fragment as decreased in APPY687A-expressing cells relative to APP wild-type (APPWT)-expressing cells, which likely reflects the different cellular localization patterns of these two proteins. Expression of APP intracellular domain (AICD) which is a cleaved product of the C83 fragment by gamma-secretase was decreased in C83Y687A-expressing cells. These results suggest that phosphorylation of APP at Tyr687 regulates APP processing by alpha- and gamma-secretases, determining the expression level of AICD. (C) 2008 Elsevier Inc. All rights reserved.