Caenorhabditis elegans as a possible model to screen anti-Alzheimer's therapeutics

Paul, Deepraj; Chipurupalli, Sandhya; Justin, Antony; Raja, Kalpana; Mohankumar, Suresh Kumar

doi:10.1016/j.vascn.2020.106932

Cited by 16 publications

(13 citation statements)

References 89 publications

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“…The applicability of transgenic C. elegans to study proteotoxicity-related diseases, such as AD and PD, has been highlighted previously (Liu et al, 2015;Paul et al, 2020). In this study, three transgenic C. elegans strains were used as models: (1) Strain CL2659 expressing Aβ in muscle cells shows a paralysis phenotype after 48 h at 25 • C and was applied to study treatments that encounter soluble Aβ oligomerization leading to a delayed onset of the paralyzed phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…In recent years, the drug discovery paradigm has shifted from single-target pharmacology to the recognition and utilization of multitarget pharmacology, whereby clinical activity is expressed as the sum of several pharmacodynamic effects on multiple targets ( Chaudhari et al, 2017 ). With increasing knowledge of drug–target interactions, more effective drugs, which modulate multiple targets, might be discovered for diseases such as PD and AD ( Wang et al, 2019 ; Mok et al, 2020 ; Paul et al, 2020 ; Zagórska and Jaromin, 2020 ; Albertini et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

et al. 2022

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Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

et al. 2022

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“…Transgenic C . elegans that expressed human Aβ 1‐42 or Tau have been constructed and used for screening anti‐AD drug, identifying the underlying molecular mechanism of the compounds and revealing the pathogenesis of AD 8‐10 …”

Section: Introductionmentioning

confidence: 99%

“…Transgenic C. elegans that expressed human Aβ 1-42 or Tau have been constructed and used for screening anti-AD drug, identifying the underlying molecular mechanism of the compounds and revealing the pathogenesis of AD. [8][9][10] Traditional Chinese medicine Polygalae Radix (Yuanzhi, Root of Polygala tenuifolia Willd.) has the efficacies of tranquillizing mind and improving the intelligence, which is often used for insomnia and amnesia.…”

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confidence: 99%

3,6'‐disinapoyl sucrose attenuates Aβ_1‐42‐ induced neurotoxicity in Caenorhabditis elegans by enhancing antioxidation and regulating autophagy

Tang

Zhao

Liu

et al. 2022

J Cellular Molecular Medi

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Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with ageing. The main clinical manifestation of AD patients is cognitive dysfunction and memory deterioration. The pathological features in the AD brain are senile plaques composed of β-amyloid (Aβ) peptide, neurofibrillary tangles composed of hyperphosphorylated tau and neuron loss. 1,2 Although the increasing number of AD patients and the high cost of treatment bring heavy burden to society and families, there are no effective treatments to cure or reverse the progress of AD except only a few drugs approved by FDA to improve the symptoms.

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“…Currently, the mammalian as an in vivo model for the selection of anti-AD drug candidates has some limitations, including the cost and time of the experiment and the number and quality of the study subjects (Alexander et al, 2014). In addition, mammalian neuronal cell culture in vitro cannot completely simulate the complexities of the human brain (Paul et al, 2020). Therefore, it is necessary to explore alternative experimental models for screening anti-AD drugs.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer’s Disease

et al. 2022

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Rehmanniae Radix (RR, the dried tuberous roots of Rehmannia glutinosa (Gaertn.) DC.) is an important traditional Chinese medicine distributed in Henan, Hebei, Inner Mongolia, and Northeast in China. RR is frequently used to treat diabetes mellitus, cardiovascular disease, osteoporosis and aging-related diseases in a class of prescriptions. The oligosaccharides and catalpol in RR have been confirmed to have neuroprotective effects. However, there are few studies on the anti-Alzheimer’s disease (AD) effect of oligosaccharides in Rehmanniae Radix (ORR). The chemical components and pharmacological effects of dried Rehmannia Radix (DRR) and prepared Rehmannia Radix (PRR) are different because of the different processing methods. ORR has neuroprotective potential, such as improving learning and memory in rats. Therefore, this study aimed to prove the importance of oligosaccharides in DRR (ODRR) and PRR (OPRR) for AD based on the Caenorhabditis elegans (C. elegans) model and the different roles of ODRR and OPRR in the treatment of AD. In this study, we used paralysis assays, lifespan and stress resistance assays, bacterial growth curve, developmental and behavioral parameters, and ability of learning and memory to explore the effects of ODRR and OPRR on anti-AD and anti-aging. Furthermore, the accumulation of reactive oxygen species (ROS); deposition of Aβ; and expression of amy-1, sir-2.1, daf-16, sod-3, skn-1, and hsp-16.2 were analyzed to confirm the efficacy of ODRR and OPRR. OPRR was more effective than ODRR in delaying the paralysis, improving learning ability, and prolonging the lifespan of C. elegans. Further mechanism studies showed that the accumulation of ROS, aggregation, and toxicity of Aβ were reduced, suggesting that ORR alleviated Aβ-induced toxicity, in part, through antioxidant activity and Aβ aggregation inhibiting. The expression of amy-1 was downregulated, and sir-2.1, daf-16, sod-3, and hsp-16.2 were upregulated. Thus, ORR could have a possible therapeutic effect on AD by modulating the expression of amy-1, sir-2.1, daf-16, sod-3, and hsp-16.2. Furthermore, ORR promoted the nuclear localization of daf-16 and further increased the expression of sod-3 and hsp-16.2, which significantly contributed to inhibiting the Aβ toxicity and enhancing oxidative stress resistance. In summary, the study provided a new idea for the development of ORR.

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Caenorhabditis elegans as a possible model to screen anti-Alzheimer's therapeutics

Cited by 16 publications

References 89 publications

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

3,6'‐disinapoyl sucrose attenuates Aβ_1‐42‐ induced neurotoxicity in Caenorhabditis elegans by enhancing antioxidation and regulating autophagy

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer’s Disease

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Caenorhabditis elegans as a possible model to screen anti-Alzheimer's therapeutics

Cited by 16 publications

References 89 publications

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans

3,6'‐disinapoyl sucrose attenuates Aβ1‐42‐ induced neurotoxicity in Caenorhabditis elegans by enhancing antioxidation and regulating autophagy

Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer’s Disease

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3,6'‐disinapoyl sucrose attenuates Aβ_1‐42‐ induced neurotoxicity in Caenorhabditis elegans by enhancing antioxidation and regulating autophagy