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Front Pharmacol
2020 Sep 10;11:553579. doi: 10.3389/fphar.2020.553579.
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Frondoside A Attenuates Amyloid-β Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation.
Tangrodchanapong T
,
Sobhon P
,
Meemon K
.
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 Aβ3â42 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 wormâs 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).
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