Insight into Amyloid Structure Using Chemical Probes

Reinke, Ashley A.; Gestwicki, Jason E.

doi:10.1111/j.1747-0285.2011.01110.x

Cited by 144 publications

(145 citation statements)

References 125 publications

(223 reference statements)

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“…Infrared spectroscopy and x-ray diffraction have demonstrated the presence of significant amounts of ␤-sheet structure in A␤42 protofibrils and fibrillar oligomers (60 -62) that appear as the earliest fibrillar aggregates within the A␤ amyloidogenic pathway (47) and are putatively a major cytotoxic A␤ species (63). It was already demonstrated that ThT recognizes prefibrillar A␤ aggregates (64) and that the ThT fluorescence was only modestly increased (1.5-fold) when compared with fibrils (Ͼ100-fold). The lower ThT fluorescence of prefibrillar or oligomeric A␤ aggregates can be explained by the lower ␤-sheet content of oligomers (ϳ48 -57%) when compared with fibrils (61).…”

Section: Discussionmentioning

confidence: 99%

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Kroth

Ansaloni

Varisco

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Kroth

Ansaloni

Varisco

et al. 2012

Journal of Biological Chemistry

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“…Aβ dimers and their EGCG complexes were resolved in the 5 + state at m/z 1,733, 1,824, and 1,916, respectively. The relative abundance of Aβ dimers was significantly increased in samples incubated with EGCG compared with Aβ samples without any additional molecules or with ThT (a fluorescent probe that binds to Aβ fibrils, but not monomers or small oligomers) (40) (Fig. 2D).…”

Section: Egcg Directly Binds To Aβ Peptide and Causes Conformational mentioning

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.

213

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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“…Some residues in Ab peptides are crucial for Ab aggregation, fibrilization, and conformational change. 35,36 Because of its Ab-binding function, DBP has a physiological significance in the pathogenesis of AD, but the contribution of the DBP-Ab interaction required elucidation. We first determined that DBP can bind to Ab and inhibit Ab oligomerization, and can influence Ab-mediated neuronal death in vitro.…”

Section: Discussionmentioning

confidence: 99%

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

et al. 2012

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The level of vitamin D-binding protein (DBP) is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD), suggesting a relationship with its pathogenesis. In this study, we investigated whether and how DBP is related to AD using several different approaches. A pull-down assay and a surface plasmon resonance binding assay indicated direct interactions between purified DBP and amyloid beta (Ab), which was confirmed in the brain of AD patients and transgenic AD model mice by immunoprecipitation assay and immunohistochemical double-staining method. Moreover, atomic force microscopic examination revealed that DBP reduced Ab aggregation in vitro. DBP also prevented Ab-mediated death in cultured mouse hippocampal HT22 cell line. Finally, DBP decreased Ab-induced synaptic loss in the hippocampus and rescued memory deficits in mice after injection of Ab into the lateral ventricle. These results provide converging evidence that DBP attenuates the harmful effects of Ab by a direct interaction, and suggest that DBP is a promising therapeutic agent for the treatment of AD.

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Insight into Amyloid Structure Using Chemical Probes

Cited by 144 publications

References 125 publications

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

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

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

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