Herein we report that a preferable inhibition of the nucleation phase of Aβ42, related to the formation of toxic oligomers, by triterpenoids from medicinal herbs originates from a salt bridge of their carboxy groups with Lys16 and 28 in Aβ42. Such a direct interaction targeting the monomer, dimer, and trimer suppressed further oligomerization. In contrast, the corresponding congeners without carboxy groups failed to do so.
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.
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