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

作者：Libeu Clare A Peters^*; Descamps Olivier; Zhang Qiang; John Varghese; Bredesen Dale E

来源：PLos One, 2012, 7(6): e40027.

DOI：10.1371/journal.pone.0040027

One of the events associated with Alzheimer's disease is the dysregulation of alpha- versus beta-cleavage of the amyloid precursor protein (APP). The product of a-cleavage (sAPP alpha) has neuroprotective properties, while A beta 1-42 peptide, a product of beta-cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of alpha- and beta-cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the alpha-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 A beta-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of A beta oligomers-which bind to dimers of the ectodomain- and A beta 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 sAPP alpha 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 alpha- to beta-cleavage of APP. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease.

• 出版日期2012-6-29