<p>Alzheimer's disease (AD) is
the most common neurodegenerative disorder, yet the cause and progression of
this disorder are not completely understood. While the main hallmark of AD is
the deposition of amyloid plaques
consisting of the β-amyloid (Aβ) peptide, transition metal ions are also
known to play a significant role in disease pathology by expediting the
formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen
species (ROS), and oxidative stress. Thus, bifunctional metal chelators that
can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural
biflavonoid compound, exhibits good metal-chelating properties, especially for chelating
Cu<sup>2+</sup> with very high affinity (pCu<sub>7.4</sub> = 10.44). In
addition, AMF binds to Aβ fibrils with a high affinity (<i>K<sub>i</sub></i> = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay,
and specifically labels the amyloid plaques <i>ex vivo</i> in the brain
sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ<sub>42</sub>
aggregation and disaggregation of Aβ<sub>42</sub> fibrils was also
investigated, to reveal that AMF can control the formation of neurotoxic
soluble Aβ<sub>42</sub> oligomers, both in absence and presence of metal ions,
and as confirmed via cell toxicity studies. Furthermore, an ascorbate
consumption assay shows that AMF exhibits potent antioxidant properties and can
chelate Cu<sup>2+</sup> and significantly diminish the Cu<sup>2+</sup>-ascorbate
redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts
as a bifunctional chelator that can interact with various Aβ aggregates and
reduce their neurotoxicity, can also bind Cu<sup>2+</sup> and mediate its
deleterious redox properties, and thus AMF has the potential to be a lead
compound for further therapeutic agent development for AD. </p>
Methionine does not reduce Cu(II)–β-amyloid!—Rectification of the roles of methionine-35 and reducing agents in metal-centered oxidation chemistry of Cu(II)–β-amyloid