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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble A?₄₂ Oligomers.

ABSTRACT: 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 ?-amyloid (A?) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble ?-amyloid (A?) 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? 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? antibody. The effect of AMF on A?₄₂ aggregation and disaggregation of A?₄₂ fibrils was also investigated and revealed that AMF can control the formation of neurotoxic soluble A?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? 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.

SUBMITTER: Sun L

PROVIDER: S-EPMC7716246 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ<sub>42</sub> Oligomers.

Sun Liang L Sharma Anuj K AK Han Byung-Hee BH Mirica Liviu M LM

ACS chemical neuroscience 20200821 17

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 ch ...[more]

PMID: 32786307

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Project description:Actinium-225 (225Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H2macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H2macropa, which contain either one (H2BZmacropa) or two (H2BZ2macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225Ac TAT. The coordination chemistry of these ligands with La3+, used as a nonradioactive model for Ac3+, was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La3+ complexes of these ligands revealed similar structural features to those found for the related complex of H2macropa. Thermodynamic stability constants of the La3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H2macropa for H2BZmacropa and H2BZ2macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225Ac radiolabeling and serum stability studies with H2BZmacropa showed that this chelator compares favorably with H2macropa. Based on these promising results, a bifunctional version of this chelator, H2BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [225Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [225Ac]Ac-GC33-macropa. Together, these results establish H2BZmacropa-NCS as a new bifunctional chelator for the preparation of 225Ac radiopharmaceuticals.

Project description:BackgroundAlzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aβ) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aβ plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aβ oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD.MethodsHippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aβ1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aβ-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aβ-treated HEBSCs.ResultsNeurotoxicity induced by soluble Aβ1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aβ-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aβ neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aβ as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aβ-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aβ-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention.ConclusionMicroglia are key mediators of both protection and neurodegeneration in response to Aβ. Polarizing microglia toward a protective state could be used as a preventative strategy against Aβ-induced neurotoxicity.

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble A?₄₂ Oligomers.

Publications

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ<sub>42</sub> Oligomers.

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble A?42 Oligomers.

Publications

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ<sub>42</sub> Oligomers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble A?₄₂ Oligomers.