Altering APP Proteolysis: Increasing sAPPalpha Production by Targeting Dimerization of the APP Ectodomain

摘要: One of the events associated with Alzheimer's disease is dysregulation α- versus β-cleavage amyloid precursor protein (APP). The product α-cleavage (sAPPα) has neuroprotective properties, while Aβ1-42 peptide, a β-cleavage, neurotoxic. Dimerization APP been shown to influence relative rate and β- cleavage APP. Thus finding compounds that interfere dimerization ectodomain increase could lead development new therapies for disease. Examining intrinsic fluorescence fragment APP, which dimerizes through E2 Aβ-cognate domains, revealed significant changes in upon binding Aβ oligomers—which bind dimers ectodomain— fragments—which destabilize ectodomain. This technique was extended show RERMS-containing peptides (APP695 328–332), disulfiram, sulfiram also inhibit fragment. activity confirmed small angle x-ray scattering. Analysis disulfiram an AlphaLISA assay indicated both significantly enhance production sAPPα by 7W-CHO B103 neuroblastoma cells. These observations demonstrate there class modulates conformation influences ratio provide rationale therapeutics