Abstract
The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer's disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF's potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.
Keywords:
2-butoxytetrahydrofuran; Alzheimer’s disease; C. elegans; H. scabra; amyloid-β; sea cucumber.
MeSH terms
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / antagonists & inhibitors*
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Animals
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Animals, Genetically Modified
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Autophagy-Related Proteins / genetics
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Autophagy-Related Proteins / metabolism
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Binding Sites
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Disease Models, Animal
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Furans / chemistry
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Furans / isolation & purification
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Furans / pharmacology*
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Gene Expression Regulation
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Holothuria / chemistry*
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Humans
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Molecular Docking Simulation
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Neuroprotective Agents / chemistry
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Neuroprotective Agents / isolation & purification
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Neuroprotective Agents / pharmacology*
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Paralysis / genetics
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Paralysis / metabolism
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Paralysis / pathology
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Paralysis / prevention & control*
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Protein Aggregates / drug effects
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Amyloid beta-Peptides
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Autophagy-Related Proteins
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Caenorhabditis elegans Proteins
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Furans
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Neuroprotective Agents
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Protein Aggregates
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Reactive Oxygen Species
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Transcription Factors
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heat shock factor-1, C elegans