title: Altering APP proteolysis: increasing sAPPalpha production by targeting dimerization of the APP ectodomain.
abstract: One of the events associated with Alzheimer's disease is the dysregulation of α- versus β-cleavage of the amyloid precursor protein (APP). The product of α-cleavage (sAPPα) has neuroprotective properties, while Aβ1-42 peptide, a product of β-cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of α- and β- cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the α-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 Aβ-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of Aβ oligomers--which bind to dimers of the ectodomain--and Aβ fragments--which destabilize dimers of the ectodomain. This technique was extended to show that RERMS-containing peptides (APP(695) 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 sAPPα by 7W-CHO and B103 neuroblastoma cells. These observations demonstrate that there is a class of compounds that modulates the conformation of the APP ectodomain and influences the ratio of α- to β-cleavage of APP. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease.
authors: Buck Institute for Research on Aging, Novato, California, United States of America. clibeu@buckinstitute.org
authors: Clare A Peters
authors: CA
authors: Libeu
authors: Olivier
authors: O
authors: Descamps
authors: Qiang
authors: Q
authors: Zhang
authors: Varghese
authors: V
authors: John
authors: Dale E
authors: DE
authors: Bredesen
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000737:chemistry*; D000817:Anilino Naphthalenesulfonates / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004221:Disulfiram / Q000031:analogs & derivatives / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry*; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D053838:Scattering, Small Angle; D014364:Tryptophan / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000817:Anilino Naphthalenesulfonates; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; C009822:monosulfiram; C027132:1-anilino-8-naphthalenesulfonate; D014364:Tryptophan; D004221:Disulfiram