Searching for Natural Products That Delay Nucleation Phase and Promote Elongation Phase of Amyloid β42 toward Alzheimer’s Disease Therapeutics

Aggregation of amyloid β42 (Aβ42) is one of the hallmarks of Alzheimer’s disease (AD). The mechanism of Aβ42 aggregation mainly consists of two phases, nucleation and elongation (including plateau region as a saturation phase). 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 nine 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. Focusing on O4 in the pursuit of anti-AD drugs, we herein screened 480 natural products including NPDepo (RIKEN) for the compounds that delayed the nucleation phase and promoted the elongation phase. The signal intensities for Aβ42 treated with each of the 15 compounds that met these criteria were lowered in dot blotting using antioligomer antibody, and the fibril formation of Aβ42 in the presence of these compounds was observed in transmission electron microscopy. Among the 15 compounds, 12 compounds (80%) reduced the toxicity of Aβ42 against mouse neuroblastoma Neuro-2a cells. Some of these anticytotoxic compounds contain 2-pyrone and 4-pyrone that interacted with Aβ42, maybe by shifting the equilibrium of Aβ from toxic oligomer into inert fibrils.