Effects of Clioquinol on Metal-Triggered Amyloid-β Aggregation Revisited

Mancino, Allana M.; Hindo, Sarmad Sahiel; Kochi, Akiko; Lim, Mi Hee

doi:10.1021/ic9014256

Cited by 95 publications

(84 citation statements)

References 29 publications

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“…3B). Compared to other metal chelators such as CQ, phen, and EDTA [phen ¼ 1;10-phenanthroline; EDTA ¼ 2;2 0 ;2 00 ;2 000 −ðethane-1;2-diyldinitriloÞtetraacetic acid] (17,22), the sample including L2-b from inhibition experiments indicated more soluble low MW Aβ species. Shortly, these inhibition experiment results could reflect that better bifunctionality of compounds (e.g., L2-b) allows for effective prevention of metal-induced Aβ aggregation.…”

Section: Modulation Of Metal-induced Aβ Aggregation By L2-a and L2-b mentioning

confidence: 89%

“…The Cu 2þ -or Zn 2þ -treated solutions of freshly prepared Aβ showed fibrillogenesis after 24 h (Fig. 3) (17,22). On the other hand, upon 24 h incubation of freshly prepared Aβ with a metal ion with L2-a or L2-b, less Aβ aggregation was presented with different morphology from that of metal-Aβ aggregates (Fig.…”

Section: Modulation Of Metal-induced Aβ Aggregation By L2-a and L2-b mentioning

confidence: 98%

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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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253

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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Section: Modulation Of Metal-induced Aβ Aggregation By L2-a and L2-b mentioning

confidence: 89%

Section: Modulation Of Metal-induced Aβ Aggregation By L2-a and L2-b mentioning

confidence: 98%

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.

Self Cite

253

420

View full text Add to dashboard Cite

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“…S2) by gel electrophoresis with Western blotting using an anti-Aβ antibody (6E10), as well as by transmission electron microscopy (TEM). These methods were used to visualize the changes in size distribution and morphology that are not accurately represented by other biological assays [e.g., thioflavin-T (ThT) assay] (37,38).…”

Section: Egcg Distinctly Modulates Aβ Aggregation Induced By Cu(ii) Omentioning

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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“…Indeed, clioquinol has shown efficacy in patients with AD and models in of disease. Clioquinol inhibits Aβ oligomer formation and protects against cell loss in an Aβ-injection model [211][212][213]. Nine weeks of oral clioquinol treatment in an AD mice lowered plaque burden and improved cognitive performance [196,214].…”

Section: Clioquinol and Pbt2mentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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Effects of Clioquinol on Metal-Triggered Amyloid-β Aggregation Revisited

Cited by 95 publications

References 29 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

Biometals and Their Therapeutic Implications in Alzheimer's Disease

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