Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 17, Pages 2741-2752Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00376
Keywords
Alzheimer's disease; amyloid plaques; biflavonoids; metal-A beta adducts; A beta oligomers; oxidative stress
Funding
- NIH [R01GM114588]
- Alzheimer's Association [NIRG 12-259199]
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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 beta-amyloid (A beta) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble beta-amyloid (A beta) 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 Cu2+ with very high affinity (pCu(7.4) = 10.44). In addition, AMF binds to A beta fibrils with a high affinity (K-i = 287 +/- 20 nM), as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice, as confirmed via immunostaining with an A beta antibody. The effect of AMF on A beta(42) aggregation and disaggregation of A beta(42) fibrils was also investigated and revealed that AMF can control the formation of neurotoxic soluble A beta(42) oligomers, both in the absence and presence of metal ions, as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu2+ and significantly diminish the Cu2+-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 A beta aggregates and reduce their neurotoxicity and can also bind Cu2+ and mediate its deleterious redox properties. Thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.
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