Recent Development of Bifunctional Small Molecules to Study Metal‐Amyloid‐<i>β</i> Species in Alzheimer′s Disease

Braymer, Joseph J.; DeToma, Alaina S.; Choi, Jung‐Suk; Ko, Kristin; Lim, Mi Hee

doi:10.4061/2011/623051

Cited by 36 publications

(63 citation statements)

References 84 publications

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“…To date, only limited efforts have been made toward this goal (2,13,(19)(20)(21)(22)(23)(24). Recently, we reported small molecules having bifunctionality (metal chelation and Aβ interaction) (22).…”

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confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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256

420

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The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...

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confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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256

420

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“…The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated. To advance our understanding of the potential neurotoxicity of metal-Aβ species, efforts to develop chemical tools capable of interacting directly with metal-Aβ species and modulating their reactivity in vitro and in biological systems are under way (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). In particular, novel bifunctional compounds that contain elements for metal chelation and Aβ interaction have recently been prepared or identified via rational structure-based design strategies or systematic selection of natural products.…”

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confidence: 99%

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Hyung¹,

DeToma²,

Brender

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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268

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Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-β (metal-Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-Aβ species are necessary, along with a fundamental understanding of their mechanism at the molecular level. Herein, we investigated and compared the interactions and reactivities of the green tea extract, (−)-epigallocatechin-3-gallate [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]-Aβ and metal-free Aβ species. We found that EGCG interacted with metal-Aβ species and formed small, unstructured Aβ aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metalfree Aβ and metal-Aβ was mitigated in living cells. To understand this reactivity at the molecular level, structural insights were obtained by ion mobility-mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. These studies indicated that (i) EGCG was bound to Aβ monomers and dimers, generating more compact peptide conformations than those from EGCGuntreated Aβ species; and (ii) ternary EGCG-metal-Aβ complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal-Aβ species with a structurebased mechanism.amyloid-β peptide | metal ions | natural products | amyloidogenesis T he brain of individuals with Alzheimer's disease (AD) has protein aggregates composed of misfolded amyloid-β (Aβ) peptides (1-4). The Aβ peptides are produced endogenously through enzymatic cleavage of amyloid precursor protein. Aβ monomers can misfold and oligomerize into various intermediates before the formation and elongation of fibrils that exhibit a characteristic cross-β-sheet structure (1-4). The accumulation of aggregated Aβ species has been a key feature of the amyloid cascade hypothesis, which cites that these aggregates are possible causative agents in AD. In addition, transition metals, such as Cu and Zn, whose misregulation leads to aberrant neuronal function, have a suggested link to AD pathology (1,(3)(4)(5)(6)(7)(8). In vitro and in vivo studies have provided evidence for the direct interactions of metal ions with Aβ and their presence within Aβ plaques, indicating the formation of metal-associated Aβ (metal-Aβ) species. These metal-Aβ species have been implicated in processes that could lead to neurotoxicity (e.g., metal-induced Aβ aggregation and metal-Aβ-mediated reactive oxygen species generation) (1, 3-8). The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated. To advance our understanding of the potential neurotoxicity of metal-Aβ species, efforts to develop chemical tools capable of interacting directly with metal-Aβ species and modulating their reactivity in vitro and in biological systems are under way (1,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)...

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“…57,62 With these results, the pursuit in biologically compatible transition metal ion ligands as therapy for AD is encouraged. 27,58 There are a multitude of challenges to overcome when designing a ligand for applications in medicinal use such as biocompatibility, specificity, and efficacy. 60 Utilizing a rational design approach, this work focuses on the use of pyclen (1) shown in Chart 1 as a metal ion passivation and antioxidant agent based on this ligand's specific metal-ion binding affinity for copper(II) and zinc(II) along with built-in antioxidant functionalities.…”

Section: 26mentioning

confidence: 99%

“…27,58−60 Synthetic targets focused on inhibiting the interactions of Aβ with metal ions, along with atypical metal ion homeostasis, are limited by ion specificity, an inability to cross the blood brain barrier (BBB), and/or biological compatibility.…”

Section: 26mentioning

confidence: 99%

See 1 more Smart Citation

An N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid Disaggregation

Lincoln

Richardson

Rutter

et al. 2012

ACS Chem. Neurosci.

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Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (Aβ) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and scanning electron microscopy imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu 2+ induced AB 1−40 aggregation. The pyridine backbone of 1 engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this aromatic feature. Finally, 1 prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using density functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity observed.

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Recent Development of Bifunctional Small Molecules to Study Metal‐Amyloid‐β Species in Alzheimer′s Disease

Cited by 36 publications

References 84 publications

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

An N-Heterocyclic Amine Chelate Capable of Antioxidant Capacity and Amyloid Disaggregation

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