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• W4365483085 abstract "Several lines of evidence suggest that a characteristic of the neuropathology of Alzheimer's disease (AD) is the aggregation of the amyloid beta peptides (Aβ), fragments of the human amyloid precursor protein (hAPP). The dominating species are the Aβ40 and Aβ42 fragments with 40 and 42 amino acids, respectively. Aβ initially forms soluble oligomers that continue to expand to protofibrils, suggestively the neurotoxic intermediates, and thereafter turn into insoluble fibrils that are markers of the disease. Using the powerful tool of pharmacophore simulation, we selected small molecules not known to possess central nervous system (CNS) activity but that might interact with Aβ aggregation, from the NCI Chemotherapeutic Agents Repository, Bethesda, MD. We assessed the activity of these compounds on Aβ aggregation using the thioflavin T fluorescence correlation spectroscopy (ThT-FCS) assay. Förster resonance energy transfer-based fluorescence correlation spectroscopy (FRET-FCS) was used to characterize the dose-dependent activity of selected compounds at an early stage of Aβ aggregation. Transmission electron microscopy (TEM) confirmed that the interfering substances block fibril formation and identified the macrostructures of Aβ aggregates formed in their presence. We first found three compounds generating protofibrils with branching and budding never observed in the control. One compound generated a two-dimensional sheet structure and another generated a double-stranded filament. Importantly, these compounds generating protofibrils with altered macrostructure protected against Aβ-induced toxicity in a cell model while showing no toxicity in a model of cognition in normal mice. The data suggest that the active compounds act as decoys turning the aggregation into nontoxic trajectories and pointing toward novel approaches to therapy." @default.
• W4365483085 created "2023-04-15" @default.
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• W4365483085 date "2023-04-14" @default.
• W4365483085 modified "2023-10-14" @default.
• W4365483085 title "Small Molecule Decoys of Aggregation for Elimination of Aβ-Peptide Toxicity" @default.
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• W4365483085 doi "https://doi.org/10.1021/acschemneuro.2c00649" @default.
• W4365483085 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37058367" @default.
• W4365483085 hasPublicationYear "2023" @default.
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