Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers.
Liang SunAnuj K SharmaByung-Hee HanLiviu M MiricaPublished in: ACS chemical neuroscience (2020)
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 Cu2+ with very high affinity (pCu7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (Ki = 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 Aβ antibody. The effect of AMF on Aβ42 aggregation and disaggregation of Aβ42 fibrils was also investigated and revealed that AMF can control the formation of neurotoxic soluble Aβ42 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 Aβ 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.
Keyphrases
- reactive oxygen species
- oxidative stress
- aqueous solution
- metal organic framework
- dna damage
- transition metal
- high throughput
- single cell
- cell death
- quantum dots
- anti inflammatory
- adipose tissue
- photodynamic therapy
- case control
- squamous cell carcinoma
- highly efficient
- type diabetes
- cell therapy
- radiation therapy
- risk assessment
- brain injury
- resting state
- mesenchymal stem cells
- ischemia reperfusion injury
- metabolic syndrome
- high resolution
- blood brain barrier
- water soluble
- lymph node
- atomic force microscopy
- heat stress