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- W2048521965 abstract "One of the key events in Alzheimer's disease is the dysregulation of alpha- versus beta-cleavage of the amyloid precursor protein (APP). The product of alpha-cleavage (sAPPα) has neuroprotective properties, while Aß 1-42 peptide, the 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 APP and increase the alpha-cleavage of APP could lead to the development of new therapies for Alzheimer's disease. Our previous work showed that binding of monomeric amyloid-beta fragments to the ectodomain of APP (eAPP) inhibited dimerization and caused large conformational changes that could be detected by small angle x-ray scattering (SAXS). Therefore, we reasoned that the intrinsic fluorescence of a fragment of eAPP (eAPP230-624), which dimerizes through the same sites as the intact ectodomain, should be sensitive to the binding of compounds that destabilize the dimerization. SAXS was used to confirm whether the compounds affected dimerization. An Alpha-LISA assay was used to determine the relative activity of the compounds in enhancing the production of sAPPα by 7W-CHO and B103 neuroblastoma cells. Examination of the intrinsic fluorescence indicated that incubation with RERMS-containing peptides (APP695 328-332), disulfiram, and sulfiram significantly perturbed the intrinsic fluorescence in a dose-dependent manner. SAXS confirmed that these compounds inhibit dimerization. Analysis of the activity of disulfiram and sulfiram in an Alpha-Lisa assay indicated that both compounds significantly enhance the production of sAPPα by 7W-CHO and B103 neuroblastoma cells. These observations indicate 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, and that methods that track the conformational changes in the eAPP230-624 in response to binding may be an effective way to identify them. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease." @default.
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- W2048521965 date "2012-07-01" @default.
- W2048521965 modified "2023-10-16" @default.
- W2048521965 title "P1-291: Increasing sAPPα levels by targeting dimerization of the APP ectodomain" @default.
- W2048521965 doi "https://doi.org/10.1016/j.jalz.2012.05.571" @default.
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