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Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid-induced oxidative stress and toxicity.

ABSTRACT: Compelling evidence shows a strong correlation between accumulation of neurotoxic ?-amyloid (A?) peptides and oxidative stress in the brains of patients afflicted with Alzheimer disease (AD). One hypothesis for this correlation involves the direct and harmful interaction of aggregated A? peptides with enzymes responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Identification of specific, destructive interactions of A? peptides with cellular anti-oxidant enzymes would represent an important step toward understanding the pathogenicity of A? peptides in AD. This report demonstrates that exposure of human neuroblastoma cells to cytotoxic preparations of aggregated A? peptides results in significant intracellular co-localization of A? with catalase, an anti-oxidant enzyme responsible for catalyzing the degradation of the ROS intermediate hydrogen peroxide (H(2)O(2)). These catalase-A? interactions deactivate catalase, resulting in increased cellular levels of H(2)O(2). Furthermore, small molecule inhibitors of catalase-amyloid interactions protect the hydrogen peroxide-degrading activity of catalase in A?-rich environments, leading to reduction of the co-localization of catalase and A? in cells, inhibition of A?-induced increases in cellular levels of H(2)O(2), and reduction of the toxicity of A? peptides. These studies, thus, provide evidence for the important role of intracellular catalase-amyloid interactions in A?-induced oxidative stress and propose a novel molecular strategy to inhibit such harmful interactions in AD.

SUBMITTER: Habib LK

PROVIDER: S-EPMC2998107 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid-induced oxidative stress and toxicity.

Habib Lila K LK Lee Michelle T C MT Yang Jerry J

The Journal of biological chemistry 20101005 50

Compelling evidence shows a strong correlation between accumulation of neurotoxic β-amyloid (Aβ) peptides and oxidative stress in the brains of patients afflicted with Alzheimer disease (AD). One hypothesis for this correlation involves the direct and harmful interaction of aggregated Aβ peptides with enzymes responsible for maintaining normal, cellular levels of reactive oxygen species (ROS). Identification of specific, destructive interactions of Aβ peptides with cellular anti-oxidant enzymes ...[more]

PMID: 20923778

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Project description:AimsThe accumulation and deposition of β-amyloid (Aβ) has always been considered a major pathological feature of Alzheimer's disease (AD). The latest and mainstream amyloid cascade hypothesis indicates that all the main pathological changes in AD are attributed to the accumulation of soluble Aβ. However, the exploration of therapeutic drugs for Aβ toxicity has progressed slowly. This study aims to investigate the protective effects of Icaritin on the Aβ-induced Drosophila AD model and its possible mechanism.MethodsTo identify the effects of Icaritin on AD, we constructed an excellent Drosophila AD model named Aβarc (arctic mutant Aβ42) Drosophila. Climbing ability, flight ability, and longevity were used to evaluate the effects of Icaritin on AD phenotypes. Aβarc was determined by immunostaining and ELISA. To identify the effects of Icaritin on oxidative stress, we performed the detection of ROS, hydrogen peroxide, MDA, SOD, catalase, GST, and Caspase-3. To identify the effects of Icaritin on energy metabolism, we performed the detection of ATP and lactate. Transcriptome analysis and qRT-PCR verifications were used to detect the genes directly involved in oxidative stress and energy metabolism. Mitochondrial structure and function were detected by an electron microscopy assay, a mitochondrial membrane potential assay, and a mitochondrial respiration assay.ResultsWe discovered that Icaritin almost completely rescues the climbing ability, flight ability, and longevity of Aβarc Drosophila. Aβarc was dramatically reduced by Icaritin treatment. We also found that Icaritin significantly reduces oxidative stress and greatly improves impaired energy metabolism. Importantly, transcriptome analysis and qRT-PCR verifications showed that many key genes, directly involved in oxidative stress and energy metabolism, are restored by Icaritin. Next, we found that Icaritin perfectly restores the integrity of mitochondrial structure and function damaged by Aβarc toxicity.ConclusionThis study suggested that Icaritin is a potential drug to deal with the toxicity of Aβarc, at least partially realized by restoring the mitochondria/oxidative stress/energy metabolism axis, and holds potential for translation to human AD.

Project description:BackgroundAscorbic acid demonstrates a cytotoxic effect by generating hydrogen peroxide, a reactive oxygen species (ROS) involved in oxidative cell stress. A panel of eleven human cancer cell lines, glioblastoma and carcinoma, were exposed to serial dilutions of ascorbic acid (5-100 mmol/L). The purpose of this study was to analyse the impact of catalase, an important hydrogen peroxide-detoxifying enzyme, on the resistance of cancer cells to ascorbic acid mediated oxidative stress.MethodsEffective concentration (EC(50)) values, which indicate the concentration of ascorbic acid that reduced the number of viable cells by 50%, were detected with the crystal violet assay. The level of intracellular catalase protein and enzyme activity was determined. Expression of catalase was silenced by catalase-specific short hairpin RNA (sh-RNA) in BT-20 breast carcinoma cells. Oxidative cell stress induced apoptosis was measured by a caspase luminescent assay.ResultsThe tested human cancer cell lines demonstrated obvious differences in their resistance to ascorbic acid mediated oxidative cell stress. Forty-five percent of the cell lines had an EC(50) > 20 mmol/L and fifty-five percent had an EC(50) < 20 mmol/L. With an EC(50) of 2.6-5.5 mmol/L, glioblastoma cells were the most susceptible cancer cell lines analysed in this study. A correlation between catalase activity and the susceptibility to ascorbic acid was observed. To study the possible protective role of catalase on the resistance of cancer cells to oxidative cell stress, the expression of catalase in the breast carcinoma cell line BT-20, which cells were highly resistant to the exposure to ascorbic acid (EC(50): 94,9 mmol/L), was silenced with specific sh-RNA. The effect was that catalase-silenced BT-20 cells (BT-20 KD-CAT) became more susceptible to high concentrations of ascorbic acid (50 and 100 mmol/L).ConclusionsFifty-five percent of the human cancer cell lines tested were unable to protect themselves against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide. Silenced catalase expression increased the susceptibility of the formerly resistant cancer cell line BT-20 to oxidative stress.

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Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid-induced oxidative stress and toxicity.

Publications

Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid-induced oxidative stress and toxicity.

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