Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice

Cherny, Robert A.; Atwood, Craig S.; Xilinas, Michel; Gray, Danielle N.; Jones, Walton D.; McLean, Catriona; Barnham, Kevin J.; Volitakis, Irene; Fraser, Fiona; Kim, Young Seon; Huang, Xudong; Goldstein, Lee E.; Moir, Robert D.; Lim, James; Beyreuther, Konrad; Zheng, Hui; Tanzi, Rudolph E.; Masters, Colin L.; Bush, Ashley I.

doi:10.1016/s0896-6273(01)00317-8

Cited by 1,374 publications

(1,227 citation statements)

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“…Since AD plaque burden starts accumulating 20 years before the onset of the disease, adequate early zinc intake may be a protective factor to slow or prevent the development of AD [101]. It has been proven that zinc therapy significantly improved patients' cognitive abilities [99], [100], [101], [102], [103], and therefore it is recommended that patients consume the Recommended Daily Allowance (RDA) of zinc without overdosing. Thus, maintaining zinc homeostasis is highly desirable for the prevention and possible treatment of AD.…”

Section: Methods Of Treating Alzheimer's Disease and Type 2 Diabetesmentioning

confidence: 99%

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

et al. 2017

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BackgroundAssociation of Alzheimer's Disease (AD) with Type 2 Diabetes (T2D) has been well established. Cyclo(His-Pro) plus zinc (Cyclo-Z) treatment ameliorated diabetes in rats and similar improvements have been seen in human patients. Treatment of amyloid precursor protein (APP) transgenic mice with Cyclo-Z exhibited memory improvements and significantly reduced Aβ-40 and Aβ-42 protein levels in the brain tissues of the mice.Scope of reviewMetabolic relationship between AD and T2D will be described with particular attention to insulin sensitivity and Aβ degradation in brain and plasma tissues. Mechanistic effect of insulin degrading enzyme (IDE) in decreasing blood glucose and brain Aβ levels will be elucidated. Cyclo-Z effects on these biochemical parameters will be discussed.Major conclusionStimulation of IDE synthesis is effective for the clinical treatment of metabolic diseases including AD and T2D.General significanceCyclo-Z might be the effective treatment of AD and T2D by stimulating IDE synthesis.

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Section: Methods Of Treating Alzheimer's Disease and Type 2 Diabetesmentioning

confidence: 99%

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

et al. 2017

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“…This side effect was only observed in Japan [195], and the association between SMON and clioquinol has since been questioned [196]. Indeed, no subsequent clinical trials have observed SMON in participants treated with clioquinol.…”

Section: Clioquinol and Pbt2mentioning

confidence: 99%

“…Clioquinol has a moderate affinity for iron, copper, and zinc (Kd Cu is 1.2×10 -10 M, Kd Zn is 7×10 -8 M) [197], and for this reason it was explored as a drug for AD. Although it was initially considered a chelator [198][199][200][201], it has more recently been characterized as a copper/zinc ionophore, which functions to redistribute these metals into cells [196,[202][203][204][205][206]. Clioquinol is still considered a moderate iron chelator as it has been shown to lower iron levels in animal models of iron overload [64,148,[207][208][209][210], and has not been shown to redistribute iron into cells using ionophore assays.…”

Section: Clioquinol and Pbt2mentioning

confidence: 99%

“…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]. In a phase 2 clinical trial of 32 patients, clioquinol prevented cognitive deterioration (Alzheimer's Disease Assessment Scale-cognitive) and lowered plasma Aβ42 levels over 36 weeks [215].…”

Section: Clioquinol and Pbt2mentioning

confidence: 99%

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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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“…[10][11][12][13] In a parallel, in-register β-sheet arrangement with sheet Hbonds oriented along the fibril axis (Figure 1a.), 3,4 the side chains of the His13 and His14 are spaced 5 Å apart along each surface of the β-sheets (Figure 1b). If the sheets are arrayed parallel to one another, the His13 and His14 side chains from different sheets are proximal, providing potential sites for Zn 2+ chelation along the sheets (Figure 1b), between the sheets (Figure 1c), or both.…”

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confidence: 99%

Modulating Amyloid Self-Assembly and Fibril Morphology with Zn(II)

et al. 2006

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Interest in the molecular structure of amyloid fibrils originates both from their association with many devastating diseases and as systems for exploring the energetics of higher order protein folding and assembly. These fibril arrays are generally viewed as rich in β-sheets, of either parallel or antiparallel orientation. [1][2][3][4][5] However, the relative arrangement of the sheets within the fibril remains poorly constrained in the existing structure models, 4,6,7 as these sheet-to-sheet arrangements are mediated predominantly by side chain packing. We now extend the use of metal ions as probes of amyloid side chain packing in simple segments of the Aβ peptide of Alzheimer's disease. By restricting the possible metal binding sites, we show that Zn 2+ can specifically control the rate of self-assembly and dramatically regulate amyloid morphology via distinct coordination environments.The histidine dyad, His13 and His14, of Aβ is implicated in metal binding 8,9 and the metalmediated toxicity of Aβ. [10][11][12][13] In a parallel, in-register β-sheet arrangement with sheet Hbonds oriented along the fibril axis (Figure 1a.), 3,4 the side chains of the His13 and His14 are spaced 5 Å apart along each surface of the β-sheets (Figure 1b). If the sheets are arrayed parallel to one another, the His13 and His14 side chains from different sheets are proximal, providing potential sites for Zn 2+ chelation along the sheets (Figure 1b), between the sheets (Figure 1c), or both. 6 Aβ(13-21), HHQKLVFFA, includes both the core segment, Aβ(17-21), known to be crucial for fibril formation, 14-18 and the metal binding dyad. To isolate His13/14 as the sole binding elements, the K16A peptide HHQALVFFA-NH 2 , Aβ(13-21)K16A, was prepared. As shown in Figure 2a, Aβ(13-21)K16A develops β-sheet secondary structure within 49 h, showing an increased mean residue molar ellipticity (MRME) by circular dichroism (CD) at 197 and 212 nm. The development of β-sheet structure was further confirmed by FTIR, showing the appearance of the amide I absorbance at 1628 cm −1 ( Figure S1a). TEM further established that Aβ(13-21)K16A assembles into fibrils (Fig. S1b), and these mature fibrils bind Congo red with the typical UV/vis absorption shift from 500 to 540 nm ( Figure S1c Figure 3). When the ribbons from the 1:1 incubation were pelleted, washed, and analyzed, the Zn 2+ to peptide ratio was 0.6-0.8 across three independent measurements. 19Wider 100-150 nm ribbons with variable twists form with longer incubation times (panels 2a, b, Figure 3). Some of the ribbons appear to coil and fuse to form tubular structures 200-300 nm in diameter (panels 2c, d, Figure 3). Therefore, Zn 2+ reduces the nucleation time of self-assembly across the entire concentration range and transforms Aβ(13-21)K16A assembly into either fibrillar or ribbon/ tubular morphology. 17 Struck by the different morphologies accessible to Aβ(13-21)-K16A, we investigated the coordination environment of Zn 2+ in the different assemblies by X-ray absorption spectroscopy (XAS). The soluble ...

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Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice

Cited by 1,374 publications

References 41 publications

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Modulating Amyloid Self-Assembly and Fibril Morphology with Zn(II)

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