Fe65 Is Not Involved in the Platelet-derived Growth Factor-induced Processing of Alzheimer's Amyloid Precursor Protein, Which Activates Its Caspase-directed Cleavage

摘要: Abstract The proteolytic processing of the precursor β-amyloid peptides (APP) is believed to be a key event in pathogenesis Alzheimer's disease. This activated through pathway involving PDGF receptor, Src, and Rac1. In this paper, we demonstrate that specifically acts on APP requires YENPTY motif present cytosolic domain. Considering several results indicate adaptor proteins interacting with domain affect APP, examined their possible involvement PDGF-induced pathway. By using an APP-Gal4 reporter system, observed overexpression Fe65 activates cleavage, whereas X11 stabilizes APP. Although mDab1 Jip1 have no effect, Shc induces strong activation contemporary exposure cells causes dramatic cooperative effect. analysis point mutations indicates function different mechanisms. fact, integrity APP695 Tyr682 residue, effect dependent upon Asn684. Furthermore, mutation Asp664 which target site for caspase-directed strongly decreases Fe65. suggests cleavage by caspases, caspase inhibitor Z-VEVD induced On contrary, effects overexpression, like those PDGF, are completely absent presence compound X require Asn684 residue APP695. regulating confirmed constitutively active dominant negative mutants Src