Forward genetic screening of a novel gene hmgs-1 Involved in Alzheimer Disease Pathogenesis in a transgenic Caenorhabditis elegans model

Li, Yuhong; Bai, Hua; Huang, Hui; Zhu, Man; Zhang, Donghua; Huang, Xiaowei

doi:10.1016/j.bbrc.2020.02.076

Cited by 3 publications

(4 citation statements)

References 14 publications

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“…Similarly, deletion of the phospholipase D gene ( pld-1 ) in an AD model overexpressing Aβ markedly improved the motor phenotype and worm size, supporting the idea that phospholipase D plays an important role in neurodegeneration [ 56 ]. Similarly, in a screening of CL4176 model mutants resistant to Aβ toxicity, the gene hmgs-1 (orthologue of human HMG-CoA synthase), whose silencing delayed worm paralysis, was discovered [ 57 ]. It has also been described that the activation of PPARα / nhr-49 (nuclear hormone receptor involved in lipid signaling) inhibits the steroid signaling pathway, which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an AD model in C. elegans [ 58 ].…”

Section: C Elegans Models To Study the Mechanism Of Toxicity...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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Section: C Elegans Models To Study the Mechanism Of Toxicity...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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“…CL4176 is a transgenic nematode that can express human Aβ1-42 protein in its muscle tissue induced by temperature and then rapidly become paralyzed, and it plays an important role in studying the pathogenesis of Alzheimer’s disease and the drugs for its treatment [ 37 , 38 ]. A paralysis assay in CL4176 worms was performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

A Rapid and Sensitive UHPLC–MS/MS Method for Determination of Chlorogenic Acid and Its Application to Distribution and Neuroprotection in Rat Brain

Bai

Zhou

et al. 2023

Pharmaceuticals

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Chlorogenic acid (5-CQA) is a phenolic natural product that has been reported to improve neurobehavioral disorders and brain injury. However, its pharmacokinetics and distribution in the rat brain remain unclear. In this study, we established a rapid and sensitive UHPLC–MS/MS method for the determination of 5-CQA in rat plasma, cerebrospinal fluid (CSF), and brain tissue to investigate whether it could pass through the blood–brain barrier (BBB) and its distribution in the rat brain, and a Caenorhabditis elegans (C. elegans) strain paralysis assay was used to investigate the neuroprotective effect of 5-CQA in different brain tissues. Chromatographic separation of 5-CQA and glycyrrhetinic acid (GA, used as internal standard) was completed in 0.5 min, and the full run time was maintained at 4.0 min. Methodological validation results presented a high accuracy (95.69–106.81%) and precision (RSD ≤ 8%), with a lower limit of quantification of 1.0 ng/mL. Pharmacokinetic results revealed that 5-CQA can pass through the BBB into the CSF, but the permeability of BBB to 5-CQA (ratio of mean AUC0-∞ of CSF to plasma) was only approximately 0.29%. In addition, 5-CQA can penetrate into the rat brain extensively and is distributed with different intensities in different nuclei. A C. elegans strain paralysis assay indicated that the neuroprotective effect of 5-CQA is positively correlated with its content in different brain tissues. In conclusion, our study for the first time explored the BBB pass rate and brain tissue distribution of 5-CQA administered via the tail vein by the UHPLC–MS/MS method and investigated the potential main target area of 5-CQA for neuroprotection, which could provide a certain basis for the treatment of nervous system-related diseases of 5-CQA.

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“…Nevertheless, some genetic, environmental, and endogenous features such as low levels of acetylcholine, excessive miss-folding and aggregation of β-amyloid (Aβ) deposits, Tau-protein aggregation, oxidative stress of reactive oxygen or nitrogen free radical species (ROS and RNS), inflammation and dyshomeostasis of bio-metal cations (Fe 2 + , Cu 2 + and Zn 2 + ) are believed to be associated with AD multifaceted pathogenesis. [3,[5][6][7][8] Currently, there is no efficient treatment for AD, but some medications alleviating the cholinergic deficit, temporarily relieve some of the symptoms. [9] Meanwhile, the inhibition of acetylcholinesterase (AChE) by benzyl piperidine derivatives such as donepezil is preferred since they are rapidly reversible, mixed competitive and noncompetitive inhibitors which interact simultaneously with the catalytic and the peripheral binding sites of AChE.…”

Section: Introductionmentioning

confidence: 99%

“…It seems that AD is a multi‐factorial disease and its accurate molecular mechanism is not fully understood. Nevertheless, some genetic, environmental, and endogenous features such as low levels of acetylcholine, excessive miss‐folding and aggregation of β‐amyloid (Aβ) deposits, Tau‐protein aggregation, oxidative stress of reactive oxygen or nitrogen free radical species (ROS and RNS), inflammation and dyshomeostasis of bio‐metal cations (Fe 2+ , Cu 2+ and Zn 2+ ) are believed to be associated with AD multifaceted pathogenesis [3,5–8] …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Molecular Docking, and Molecular Dynamics Simulation Studies of Novel 3‐Hydroxypyridine‐4‐one Derivatives as Potential Acetylcholinesterase Inhibitors

Asgarshamsi

Dehkordi

Fassihi

2023

Chemistry & Biodiversity

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Researchers have focused on inhibiting acetylcholinesterase for Alzheimer's disease treatment. In this study, some novel AChE inhibitors were synthesized using hydroxypyridin‐4‐one plus benzylpiperidine scaffolds which were evaluated using Ellman's method. Accordingly, ((1‐(4‐methoxyphenethyl)piperidin‐4‐yl)amino)methyl)‐5‐hydroxy‐1‐methylpyridin‐4(1H)‐one (VIId) showed weaker but promising AChE inhibition compared to donepezil (IC50=143.090 nM). The average RMSD values of VIId was found to be 2.25 indicated less structural changes in the active site residues. The phenyl group of the phenyl‐ethyl‐N‐piperidine moiety of VIId formed hydrophobic interactions with Trp285 and Tyr340. There was a π‐cation interaction between nitrogen atom of piperidine ring and Phe294. Another π‐cation interaction was found between type 2 amine of linker and Trp85. Piperidine ring interacted with Tyr336, Tyr123, and Phe337 through hydrophobic interactions. Indeed, the VIId was predicted to be absorbed across the gastrointestinal tract, though it may be pumped out by P‐gp. Indeed, VIId can permeate through the blood brain barrier. MD simulation studies revealed that benzyloxy moiety plays a role similar to benzylpiperidine moiety of donepezil in binding to the active site residues. Also, carbonyl group functioned similar to indanone ketone group. Overall; further research on VIId may lead to introduction of a novel class of AChE inhibitors.

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Forward genetic screening of a novel gene hmgs-1 Involved in Alzheimer Disease Pathogenesis in a transgenic Caenorhabditis elegans model

Cited by 3 publications

References 14 publications

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Modeling Alzheimer’s Disease in Caenorhabditis elegans

A Rapid and Sensitive UHPLC–MS/MS Method for Determination of Chlorogenic Acid and Its Application to Distribution and Neuroprotection in Rat Brain

Design, Synthesis, Molecular Docking, and Molecular Dynamics Simulation Studies of Novel 3‐Hydroxypyridine‐4‐one Derivatives as Potential Acetylcholinesterase Inhibitors

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