Classification of amyloid β42 aggregation modulators from natural product library identifies promising scaffolds that suppress nuclei‐driven neurotoxicity

Abstract

AbstractBackgroundThe mechanism of Aβ42 aggregation mainly consists of two phases, nucleation and elongation (including a plateau region). During the nucleation phase, the monomer gradually forms toxic oligomers. During the elongation phase, each nucleus acts as a template and associates with monomers to initiate less‐toxic fibrillization. We previously proposed a method of classifying compounds into 9 groups based on their ability to modulate the nucleation and/or elongation phases. An orcein derivative (O4), which is a phenoxazine dye isolated from the lichen Roccella tinctoria and containing a 2,5‐cyclohexadienone moiety, was reported to convert oligomers into relatively inert fibrils, resulting in the reduction of the neurotoxicity of Aβ42 (Bieschke, J., et al. Nat. Chem. Biol. 2011, 8, 93‐101). Focusing on O4 in the pursuit of anti‐AD drugs, we herein screened 480 natural products including NPDepo (RIKEN).MethodThe ability of Aβ42 to aggregate or oligomerize was evaluated by thioflavin‐T fluorescence assay, transmission electron microscopy, and dot blotting. The neurotoxicity of Aβ42 was tested by MTT assay on mouse neuroblastoma Neuro2a cells.ResultThe 15 compounds that met the criteria of both delaying the nucleation phase and promoting the elongation phase were selected, and the signal intensities for Aβ42 oligomer treated with each of these compounds were lowered in dot blotting using anti‐oligomer antibody. On the other hand, the fibril formation of Aβ42 in the presence of these compounds was observed. Moreover, among the 15 compounds, 12 compounds (80%) reduced Aβ42‐induced toxicity.ConclusionGiven that some of these anti‐cytotoxic compounds such as warfarin contain 2‐pyrone or 4‐pyrone moiety as does O4, the current data suggest that hit compounds can shift the equilibrium of Aβ42 from toxic oligomer into less‐toxic fibrils by forming Michael adduct with Aβ42.