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: Clare A Peters Libeu, Olivier Descamps, Qiang Zhang, Varghese John, Dale E Bredesen
• Journal: PloS one (PLoS One) Vol. 7 Issue 6 Pg. e40027 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22768208 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Anilino Naphthalenesulfonates
• Peptide Fragments
• Peptides
• Recombinant Fusion Proteins
• monosulfiram
• 1-anilino-8-naphthalenesulfonate
• Tryptophan
• Disulfiram

Topics

• Amyloid beta-Protein Precursor (biosynthesis, chemistry)
• Anilino Naphthalenesulfonates (metabolism)
• Animals
• CHO Cells
• Cricetinae
• Disulfiram (analogs & derivatives, metabolism)
• Fluorescence
• Humans
• Models, Molecular
• Peptide Fragments (biosynthesis, chemistry)
• Peptides (metabolism)
• Protein Binding
• Protein Multimerization
• Protein Structure, Tertiary
• Proteolysis
• Rats
• Recombinant Fusion Proteins (metabolism)
• Scattering, Small Angle
• Tryptophan (metabolism)
• X-Ray Diffraction