Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Front Pharmacol
2020 Sep 10;11:553579. doi: 10.3389/fphar.2020.553579.
Show Gene links
Show Anatomy links
Frondoside A Attenuates Amyloid-β Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation.
Tangrodchanapong T
,
Sobhon P
,
Meemon K
.
???displayArticle.abstract???
Oligomeric assembly of Amyloid-β (Aβ) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of Aβ oligomers could halt the disease progression. In this study, by using transgenic Caenorhabditis elegans model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber Cucumaria frondosa saponin with anti-cancer activity, on Aβ aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 µM significantly delayed the worm paralysis caused by Aβ aggregation as compared with control group. In addition, the number of Aβ plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of Aβ species in the transgenic C. elegans were significantly reduced upon treatment with frondoside A, whereas the level of Aβ monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of Aβ. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express Aβ. Taken together, these data suggested that low dose of frondoside A could protect against Aβ-induced toxicity by primarily suppressing the formation of Aβ oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-Aβ aggregation should be studied and elucidated in the future.
Figure 1. Effect of frondoside A on Aβ-induced paralysis in CL4176 transgenic C. elegans strain. (A) Structure of frondoside A. (B) Diagram illustrating the paralysis assays showing the time at which the temperature was raised in C. elegans CL4176 and CL802 (control strain) and duration of worms fed with frondoside A in different treatment plans. (C) Time course of Aβ-induced paralysis in transgenic C. elegans strains fed with vehicle control (Ctrl) or various concentrations of frondoside A (0.05, 0.1, 0.25, 0.5, 1, 10, and 20 µM) or ginsenoside-Rg3 at 50 µM in all treatment regimen. The paralysis was scored at 2-h intervals. Data are expressed as percentages ± SD of unparalyzed worms from three independent assays with at least 100 worms in each experiment. (D) The paralysis index (PT50) was quantified as a mean of duration at which 50% worms treated with or without compounds were paralyzed. (E) Dose-response effect of frondoside A on Aβ-induced paralysis in CL4176 worms. Error bars indicate SD (*p < 0.05 compared with untreated control CL4176 worms).
Figure 2. Effect of frondoside A on Aβ-induced paralysis in CL2006 transgenic C. elegans strain. (A) Time course of paralysis caused by constitutive Aβ3–42 expression in CL2006 worms fed with vehicle control (Ctrl) or various concentrations of frondoside A (0.05, 0.1, 0.25, 0.5, 1, 10, and 20 µM). The paralysis was scored every day. Data are expressed as percentages ± SD of unparalyzed worms from three independent assays with at least 100 worms in each experiment. (B) The paralysis index (PT50) indicates quantification of a mean time at which 50% worms treated with or without compound were paralyzed. Error bars indicate SD (*p < 0.05 and ***p < 0.001 compared with untreated control CL2006 worms).
Figure 3. Effect of frondoside A on Aβ species in C. elegans strains. (A) Representative western blot of low molecular weight Aβ species in CL4176 and CL2006 worms fed with either vehicle or 1 µM frondoside A and detected by anti-Aβ antibody (6E10) or anti-actin. Quantification of Aβ monomers at 4 kDa (B), Aβ oligomers at 20 kDa (C), and 25 kDa (D) in both CL4176 and CL2006 fed with frondoside A or vehicle was analyzed by using Image J software. (E) Representative western blot of high molecular weights of Aβ species in untreated and treated CL2006 worm tissues as detected by 6E10 antibody. The Aβ oligomer bands at 60, 75, 100, and 150 kDa were quantified (F). The black lines indicate various molecular sizes of Aβ oligomers. The arrows indicate Aβ monomers (4 kDa) or actin (43 kDa). Quantitative data are expressed as mean ± SD of the indicated band density from three independent experiments (exp) with 1,000 worms in each group. *p < 0.05 and **p < 0.01 vs. control group.
Figure 4. Aβ deposits in transgenic C. elegans CL2006 fed with or without frondoside A. Representative images of X-34 staining in the C. elegans wild-type N2 (A) and transgenic strain CL2006 treated with vehicle (B) or frondoside A at 1 µM (C) or ginsenoside-Rg3 at 50 µM (D). White arrows indicate Aβ reactive deposits in the worm head, which is separated from body by pharyngeal bulb region (black arrows). Scale bar represents 20 µm. (E) Quantitative analysis of Aβ deposits in the head region of transgenic strain CL2006 compared between control (Ctrl) and different treatment groups. The quantity is expressed as mean number ± SEM of Aβ deposits/area of the individual worm’s head region from three different assays with a total of 69 worms (23 worms for each analysis) (***p < 0.001).
Figure 5. Effect of frondoside A on reactive oxygen species (ROS) in transgenic C. elegans fed with vehicle or frondoside A (0.1, 1, 10, and 20 µM) or ginsenoside-Rg3 (50 µM). Synchronized CL4176 and its control strain CL802 maintained at 16°C for 36 h were temperature upshifted to 25°C for 36 h followed by the DCF assay for ROS detection. The representative data are shown as percentage of fluorescence (%DCF) relative to vehicle-treated CL4176 controls (Ctrl), which is set as 100%. Error bars indicate SEM (three independent assays with 60 worms in each group, **p < 0.01 compared with control group).
Figure 6. Assays for chemotaxis behavior in neuronal Aβ-expressing strain CL2355. (A) Schematic diagram of chemotaxis assay. After treatment, C. elegans CL2355 and CL2122 control strain were placed on the center of the assay plate and incubated for 1 h. The worms migrated to each quadrant (A&D with chemical attractant, B&C for control without attractant) were scored and calculated for chemotactic index (CI). (B) Data represent CI ± SD in neuronal Aβ strain CL2355 and CL2122 treated with vehicle or different concentrations of frondoside A ranging from 0.1 to 20 µM. The results are obtained from three independent experiments with 60 worms in each group (*p < 0.05 compared with control group).
Al Marzouqi,
Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.
2011, Pubmed,
Echinobase
Al Marzouqi,
Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.
2011,
Pubmed
,
Echinobase
Aminin,
Immunomodulatory properties of frondoside A, a major triterpene glycoside from the North Atlantic commercially harvested sea cucumber Cucumaria frondosa.
2008,
Pubmed
,
Echinobase
Aminin,
Immunomodulatory effects of holothurian triterpene glycosides on mammalian splenocytes determined by mass spectrometric proteome analysis.
2009,
Pubmed
Aminin,
Immunomodulatory action of monosulfated triterpene glycosides from the sea cucumber Cucumaria okhotensis: stimulation of activity of mouse peritoneal macrophages.
2010,
Pubmed
,
Echinobase
Artal-Sanz,
Caenorhabditis elegans: a versatile platform for drug discovery.
2006,
Pubmed
Benilova,
The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes.
2012,
Pubmed
Bitan,
Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways.
2003,
Pubmed
Brookmeyer,
Forecasting the global burden of Alzheimer's disease.
2007,
Pubmed
Brothers,
The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease.
2018,
Pubmed
Butterfield,
beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer's disease.
1997,
Pubmed
Chen,
Reductions in levels of the Alzheimer's amyloid beta peptide after oral administration of ginsenosides.
2006,
Pubmed
Chuang,
Amyloid assembly and disassembly.
2018,
Pubmed
Citron,
Alzheimer's disease: strategies for disease modification.
2010,
Pubmed
Diomede,
Tetracycline and its analogues protect Caenorhabditis elegans from β amyloid-induced toxicity by targeting oligomers.
2010,
Pubmed
Diomede,
Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.
2013,
Pubmed
Drake,
Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model.
2003,
Pubmed
Dyshlovoy,
The marine triterpene glycoside frondoside A exhibits activity in vitro and in vivo in prostate cancer.
2016,
Pubmed
Eisenberg,
The amyloid state of proteins in human diseases.
2012,
Pubmed
Garcia-Osta,
Amyloid beta mediates memory formation.
2009,
Pubmed
Guo,
Cranberry Extract Standardized for Proanthocyanidins Alleviates β-Amyloid Peptide Toxicity by Improving Proteostasis Through HSF-1 in Caenorhabditis elegans Model of Alzheimer's Disease.
2016,
Pubmed
Haass,
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
2007,
Pubmed
Hobert,
Behavioral plasticity in C. elegans: paradigms, circuits, genes.
2003,
Pubmed
Joo,
Potential effects of microglial activation induced by ginsenoside Rg3 in rat primary culture: enhancement of type A Macrophage Scavenger Receptor expression.
2005,
Pubmed
Karamanos,
Mechanisms of amyloid formation revealed by solution NMR.
2015,
Pubmed
Kayed,
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.
2003,
Pubmed
Kienlen-Campard,
Intracellular amyloid-beta 1-42, but not extracellular soluble amyloid-beta peptides, induces neuronal apoptosis.
2002,
Pubmed
Kim,
A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system.
2013,
Pubmed
LaFerla,
Intracellular amyloid-beta in Alzheimer's disease.
2007,
Pubmed
Larson,
Soluble Aβ oligomer production and toxicity.
2012,
Pubmed
Link,
Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34.
2001,
Pubmed
Link,
Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model.
2003,
Pubmed
Lublin,
Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity.
2013,
Pubmed
Margie,
C. elegans chemotaxis assay.
2013,
Pubmed
Masters,
Alzheimer's disease.
2015,
Pubmed
McColl,
The Caenorhabditis elegans A beta 1-42 model of Alzheimer disease predominantly expresses A beta 3-42.
2009,
Pubmed
Nimmrich,
Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid.
2009,
Pubmed
Park,
Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers.
2014,
Pubmed
,
Echinobase
Puzzo,
Amyloid-β peptide: Dr. Jekyll or Mr. Hyde?
2013,
Pubmed
Salminen,
Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer's pathology.
2008,
Pubmed
Sangha,
Liuwei Dihuang (LWDH), a traditional Chinese medicinal formula, protects against β-amyloid toxicity in transgenic Caenorhabditis elegans.
2012,
Pubmed
Smith,
Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761.
2003,
Pubmed
Sultana,
Oxidatively modified proteins in Alzheimer's disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis.
2009,
Pubmed
Tanaka,
Cytoplasmic p21(Cip1/WAF1) regulates neurite remodeling by inhibiting Rho-kinase activity.
2002,
Pubmed
Tarasoff-Conway,
Clearance systems in the brain-implications for Alzheimer disease.
2015,
Pubmed
Taylor,
Development of a proteolytically stable retro-inverso peptide inhibitor of beta-amyloid oligomerization as a potential novel treatment for Alzheimer's disease.
2010,
Pubmed
Umeda,
Intracellular amyloid β oligomers impair organelle transport and induce dendritic spine loss in primary neurons.
2015,
Pubmed
Upadhaya,
High-molecular weight Aβ oligomers and protofibrils are the predominant Aβ species in the native soluble protein fraction of the AD brain.
2012,
Pubmed
Urbanc,
In silico study of amyloid beta-protein folding and oligomerization.
2004,
Pubmed
Wu,
Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans.
2006,
Pubmed
Wu,
Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers.
2010,
Pubmed
Yano,
Involvement of Hu and heterogeneous nuclear ribonucleoprotein K in neuronal differentiation through p21 mRNA post-transcriptional regulation.
2005,
Pubmed
Zhang,
Scorpion Venom Heat-Resistant Peptide Protects Transgenic Caenorhabditis elegans from β-Amyloid Toxicity.
2016,
Pubmed
