Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans

Gutierrez-Zepeda, Astrid; Santell, Ross; Wu, Zhixin; Brown, Marishka K.; Wu, Yinong; Khan, Ikhlas A.; Link, Christopher D.; Zhao, Baolu; Luo, Yuan

doi:10.1186/1471-2202-6-54

Cited by 123 publications

(54 citation statements)

References 61 publications

(63 reference statements)

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“…The increased production of superoxide precedes the paralysis in the transgenic C. elegans CL2006 strain constitutively expressing the human Aβ 3–42 peptide [45], [46]; this was observed under experimental conditions (+64% of superoxide production in CL2006 worms as compared to the CL802 control strain. p <0.001, Student’s t-test, n = 100 worms/group).…”

Section: Resultsmentioning

confidence: 83%

Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

et al. 2013

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The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer’s disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

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Section: Resultsmentioning

confidence: 83%

Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

et al. 2013

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“…Oxidative stress is known to occur in transgenic C. elegans strains expressing amyloidogenic proteins [29], [30]. We determined superoxide production in β 2 -m expressing worms at L3/L4 larval stage.…”

Section: Resultsmentioning

confidence: 99%

C. elegans Expressing Human β2-Microglobulin: A Novel Model for Studying the Relationship between the Molecular Assembly and the Toxic Phenotype

et al. 2012

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Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β2-microglobulin (β2-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β2-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β2-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β2-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β2-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β2-m.

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“…These include natural compounds such gingko biloba extract [12], the soy isoflavone glycitein [13], and epigallocatechin gallate [14]. Drug-related compounds including reserpine [15], fluoxetine [16], and thioflavin T [17], have also been shown to modulate toxicity in this model.…”

Section: Alzheimer’s Disease Modeled In C Elegansmentioning

confidence: 99%

Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity

Lublin

Link

2013

Drug Discovery Today: Technologies

100

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Alzheimer’s disease (AD) is a complex human neurodegenerative disease. Currently the therapeutics for AD only treat the symptoms. While numbers of excellent studies have used mammalian models to discover new compounds, the time and effort involved with screening large numbers of candidates is prohibitive. Cultured mammalian neurons are of often used to perform high through-put screens (HTS) however, cell culture lacks the organismal complexity involved in AD. To address these issues a number of researchers are turning to the round worm, C. elegans. C. elegans has numerous models of both Tau and Aβ induced toxicity; the two prime components observed to correlate with AD pathology. These models have lead to the discovery of numerous AD modulating candidates. Further, the ease of performing RNAi for any gene in the C. elegans genome allows for identification of proteins involved in the mechanism of drug action. These attributes make C. elegans well positioned to aid in the discovery of new AD therapies.

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Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans

Cited by 123 publications

References 61 publications

Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

C. elegans Expressing Human β2-Microglobulin: A Novel Model for Studying the Relationship between the Molecular Assembly and the Toxic Phenotype

Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity

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