Metal-associated amyloid-β species in Alzheimer's disease

Pithadia, Amit S.; Lim, Mi Hee

doi:10.1016/j.cbpa.2012.01.016

Cited by 245 publications

(192 citation statements)

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“…According to the docking results, EGCG had a tendency to associate with Aβ primarily near the hydrophilic N-terminus and the α-helical region spanning residues H13 to D23 (46). This binding pocket is near the H6, H13, and H14 residues that may be responsible for metal binding to Aβ, as well as to residues in the hydrophobic self-recognition sequence, suggested to be linked to Aβ aggregation pathways (1,3,8,(47)(48)(49). A combination of polar (e.g., hydrogen bonding, electrostatic interaction) and hydrophobic interactions was likely responsible for the close proximity of EGCG to hydrophilic and hydrophobic portions of Aβ in solution.…”

Section: Molecular Modeling Studies Present That Egcg Could Interact mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

“…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)(4)(5)(6)(7)(8). The involvement of metal-Aβ species in AD pathogenesis, however, has not been clearly elucidated.…”

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confidence: 99%

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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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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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Section: Molecular Modeling Studies Present That Egcg Could Interact mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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219

268

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“…However, excessive Al 3+ in human body may cause damage to nucleic acids and proteins or the central nervous system [28][29][30]. Thus, it is important to detect Al 3+ with high selectivity and sensitivity, both in the environment and organisms [31,32].…”

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confidence: 99%

A europium(III) metal-organic framework as ratiometric turn-on luminescent sensor for Al3+ ions

Cheng

Chen

et al. 2018

Sci. China Mater.

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In recent years, luminescent metal-organic frameworks (MOFs) as a new type of sensing material are receiving enormous attention for their superior performance in chemical sensors and biosensors [1][2]. Taking account of the excellent optical properties such as large Stokes shifts and high color purity of lanthanide MOFs (LnMOFs), a great deal of important investigations on LnMOFs have been carried out. And then, their promising abilities in detecting temperature, metal ions, oxygen, explosives and polychlorizated benzenes with high sensitivity and selectivity have also been exploited successfully [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Ratiometric luminescent sensors can provide a self-calibrated analyte concentration readout, which is unaffected by fluctuations of sensor concentration and/or instrumental parameters. However, it is noticed that a majority of related reports are limited to the detection of analyte using single emission, although ratiometric sensors based on dual-emission are more reliable and accurate than the sensors based on single emission. For ratiometric sensors, not only are two significantly different emissions necessary, but two emissions need distinctive response to the analyte. From this point of view, LnMOFs with ligand and Ln 3+ emissions are very attractive, because organic ligands and Ln 3+ ions as the luminescent centers possess completely different physical and chemical properties and they would produce different interactions with analytes. Thus, LnMOFs have been extensively applied to construct ratiometric sensors recently [3,22].Aluminium exists in soil, containers and structural materials, which may release Al 3+ due to the corrosion and/or dissolvation, inducing the increasing risk of Al 3+ absorption by the human body [23][24][25][26][27]. However, excessive Al 3+ in human body may cause damage to nucleic acids and proteins or the central nervous system [28][29][30]. Thus, it is important to detect Al 3+ with high selectivity and sensitivity, both in the environment and organisms [31,32]. As far as we are concerned, few LnMOFs display high selectivity and sensitivity for Al 3+ [33][34][35]. It is noted that Al 3+ may replace the Ln 3+ in the framework or interact with the ligands [36]. As a consequence, both ligand and Ln 3+ emissions may be interfered by Al 3+ ions. These facts impel us to realize LnMOFs ratiometric sensors for Al 3+ by the judicious choice of the organic ligand. Recently, a few works reported different fluorescence response behavior to Al 3+ ions for the emissions of the ligand and Tb 3+ ion [37,38]. In these cases, the Tb 3+ emission decreases gradually, whereas the ligand emission shows a strong enhancement as the addition of Al 3+ ions. Inspired by these cases, we aimed to synthesize LnMOFs as ratiometric luminescent sensors to detect Al 3+ ions.In this work, three Ln-MOFs, (Me 2 NH 2 )[Ln 2 L 2 (NO 3 ) 2 -(μ 3 -OH)(H 2 O)]·2H 2 O·2DMA, [Ln=Eu(1), Gd(2) and Tb (3), DMA=dimethylacetamide], were obtained based on a robust...

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Ligand Design to Target and Modulate Metal–Protein Interactions in Neurodegenerative Diseases

Beck

Pithadia

DeToma

et al. 2014

Ligand Design in Medicinal Inorganic Chemistry

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Metal-associated amyloid-β species in Alzheimer's disease

Cited by 245 publications

References 44 publications

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

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

A europium(III) metal-organic framework as ratiometric turn-on luminescent sensor for Al3+ ions

Ligand Design to Target and Modulate Metal–Protein Interactions in Neurodegenerative Diseases

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