altering app proteolysis increasing sappalpha production by targeting dimerization of the app ectodomain改变应用程序针对二聚作用的蛋白水解作用增加sappalpha生产应用ectodomain.pdfVIP

Altering APP Proteolysis: Increasing sAPPalpha Production by Targeting Dimerization of the APP Ectodomain Clare A. Peters Libeu*, Olivier Descamps, Qiang Zhang, Varghese John, Dale E. Bredesen Buck Institute for Research on Aging, Novato, California, United States of America Abstract One of the events associated with Alzheimer’s disease is the dysregulation of a- versus b-cleavage of the amyloid precursor protein (APP). The product of a-cleavage (sAPPa) has neuroprotective properties, while A b1-42 peptide, a product of b- cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of a- and b- cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the a-cleavage of APP could lead to the development of new therapies for Alzheimer’s disease. Examining the intrinsic fluorescence of a fragment of the ectodomain of APP, which dimerizes through the E2 and Ab-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of A b oligomers—which bind to dimers of the ectodomain— and Ab fragments—which destabilize dimers of the ectodomain. This technique was extended to show that RERMS-containing peptides (APP695 328–332), disulfiram, and sulfiram also inhibit dimerization of the ectodomain fragment. This activity was confirmed with small angle x-ray scattering. Analysis of the activity of disulfiram and sulfiram in an AlphaLISA assay indicated that both compounds significantly enhance the production of sAPPa by 7W-CHO and B103 neuroblastoma cells. These observations demonstrate that there is a class of compounds that modulates the conformation of the APP