A prochelator activated by hydrogen peroxide prevents metal-induced amyloid Beta aggregation.
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ABSTRACT:
SUBMITTER: Dickens MG
PROVIDER: S-EPMC2863026 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
Publications
A prochelator activated by hydrogen peroxide prevents metal-induced amyloid Beta aggregation.
Dickens Marina G MG Franz Katherine J KJ
Chembiochem : a European journal of chemical biology 20100101 1
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Project description: Not available
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Project description:Described here is the development of two boronic ester-based fluorescent prochelators, FloB (2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4(5)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene-hydrazinocarbonyl]-benzoic acid) and FloB-SI (2-(6-hydroxy-3-oxo-3Hxanthen-9-yl)-4(5)-[2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)-benzylidene-hydrazinocarbonyl]-benzoic acid) that show a fluorescence response to a variety of transition metal ions only after reaction with H(2)O(2). Both prochelators' boronic ester masks are oxidized by H(2)O(2) to reveal a fluorescein-tagged metal chelator, FloS (4(5)-(2-hydroxy-benzylidenehydrazinocarbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-benzoic acid). Chelation of Fe(3+) or Cu(2+) elicits a 70% decrease in the emission signal of FloS, while Zn(2+), Ni(2+), and Co(2+) produce a more modest fluorescence decrease. The conversion of FloB to FloS proceeds in organic solvents, but hydrolytic decomposition of its hydrazone backbone is observed in aqueous solution. However, FloB-SI oxidizes cleanly with H(2)O(2) within 1 h in aqueous solutions to produce FloS. Fluorescence microscopy studies in HeLa cells with FloB-SI show that the sensor's fluorescence intensity remains unchanged until incubation with exogenous H(2)O(2), which results in a decreased fluorescent signal. Incubation with a competitive chelator restores the emission response, thus suggesting that FloB-SI can effectively report on a H(2)O(2)-induced increase in intracellular labilized metal.
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Project description:The intersection of the amyloid cascade hypothesis and the implication of metal ions in Alzheimer's disease progression has sparked an interest in using metal-binding compounds as potential therapeutic agents. In the present work, we describe a prochelator SWH that is enzymatically activated by beta-secretase to produce a high affinity copper chelator CP. Because beta-secretase is responsible for the amyloidogenic processing of the amyloid precursor protein, this prochelator strategy imparts disease specificity toward copper chelation not possible with general metal chelators. Furthermore, once activated, CP efficiently sequesters copper from amyloid-beta, prevents and disassembles copper-induced amyloid-beta aggregation, and diminishes copper-promoted reactive oxygen species formation.
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Project description:Dysregulation of localized iron homeostasis is implicated in several degenerative diseases, including Parkinson's, Alzheimer's, and age-related macular degeneration, wherein iron-mediated oxidative stress is hypothesized to contribute to cell death. Inhibiting toxic iron without altering normal metal-dependent processes presents significant challenges for standard small molecule chelating agents. We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelators that are converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) chelating agents that inhibit iron-catalyzed hydroxyl radical generation. Here, we show that BSIH protects a cultured cell model for retinal pigment epithelium against cell death induced by hydrogen peroxide. BSIH is more stable than SIH in cell culture medium and is more protective during long-term experiments. Repetitive exposure of cells to BSIH is nontoxic, whereas SIH and desferrioxamine induce cell death after repeated exposure. Combined, our results indicate that cell protection by BSIH involves iron sequestration that occurs only when the cells are stressed by hydrogen peroxide. These findings suggest that prochelators discriminate toxic iron from healthy iron and are promising candidates for neuro- and retinal protection.
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Project description:The aggregation or misfolding of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). The regulation of Aβ aggregation is thought to be an effective strategy for AD treatment. The capability of a water-soluble porphyrin, 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP), to inhibit Aβ aggregation and to lower Aβ-induced toxicity was demonstrated. As evidenced by surface plasmon resonance and circular dichroism, TMPyP can not only disrupt Aβ aggregation but also disassemble the preformed Aβ aggregates. The atomic force microscopy imaging proves that TMPyP inhibits the formation of both oligomers and fibrils. Molecular dynamic simulations provide an insight into the interaction between TMPyP and Aβ at the molecular level. The half-maximal inhibitory concentrations of TMPyP acting on the oligomers and fibrils were determined to be 0.6 and 0.43 μM, respectively. As a member of porphyrin family, TMPyP is of rather low cytotoxicity, and the cytotoxicity of the Aβ aggregates was also relieved upon coincubation with TMPyP. The excellent performance of TMPyP thus makes it a potential drug candidate for AD therapy.
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Project description:The discovery of effective therapeutics targeting amyloid-β (Aβ) aggregates for Alzheimer's disease (AD) has been very challenging, which suggests its complicated etiology associated with multiple pathogenic elements. In AD-affected brains, highly concentrated metals, such as copper and zinc, are found in senile plaques mainly composed of Aβ aggregates. These metal ions are coordinated to Aβ and affect its aggregation and toxicity profiles. In this review, we illustrate the current view on molecular insights into the assembly of Aβ peptides in the absence and presence of metal ions as well as the effect of metal ions on their toxicity.
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