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Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced by restricted cholesterol supply.
Neurosci Lett. 2014 Jul 25; 576:93-6.NL

Abstract

Alzheimer' disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). This process is influenced through supply of cholesterol via apolipoproteins to neurons. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, which expresses Aβ1-42 under control of a muscle-specific promoter, to test the effects of the apolipoprotein B homologue vitellogenin-6 on paralysis. Knockdown of vitellogenin-6 using RNA-interference (RNAi) recently was shown to significantly reduce cholesterol absorption in C. elegans, and both, RNAi for vitellogenin-6 or lowering the cholesterol concentration in the medium was associated with reduced Aβ-aggregation and paralysis in the nematodes. The effects of both interventions are mediated through the inhibition of the steroidal-signaling pathway since knockdown of its key factors DAF-9 or DAF-12 reduced paralysis independent of the cholesterol concentration and without additive effects by vitellogenin-6 RNAi. Double-RNAi for daf-12 and the downstream target of insulin-signaling, the foxo transcription factor daf-16, revealed that the paralysis-triggering effects of daf-16 RNAi were dominant over the preventive effects of daf-12 RNAi. Identical observations were made when the transcriptional co-activators of DAF-16, ftt-2 or par-5 were knocked down instead of daf-16. In conclusion, interactions between the steroidal and insulin-signaling pathways were identified in Aβ1-42 expressing CL2006, where cholesterol deprivation inhibits steroidal-signaling and thereby activates DAF-16-signaling. Those effects were associated with a reduced Alzheimer phenotype in the nematodes, i.e. reduced protein aggregation and paralysis.

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Authors+Show Affiliations

Regitz C
Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
Wenzel U
Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany. Electronic address: uwe.wenzel@ernaehrung.uni-giessen.de.

MeSH

Amyloid beta-PeptidesAnimalsAnimals, Genetically ModifiedCaenorhabditis elegansCaenorhabditis elegans ProteinsCholesterolCytochrome P-450 Enzyme SystemHumansMovementPeptide FragmentsProtein AggregatesRNA InterferenceReceptors, Cytoplasmic and NuclearSignal TransductionVitellogenins

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24909620

Citation

Regitz, Charlotte, and Uwe Wenzel. "Amyloid-beta (Aβ1-42)-induced Paralysis in Caenorhabditis Elegans Is Reduced By Restricted Cholesterol Supply." Neuroscience Letters, vol. 576, 2014, pp. 93-6.
Regitz C, Wenzel U. Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced by restricted cholesterol supply. Neurosci Lett. 2014;576:93-6.
Regitz, C., & Wenzel, U. (2014). Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced by restricted cholesterol supply. Neuroscience Letters, 576, 93-6. https://doi.org/10.1016/j.neulet.2014.05.059
Regitz C, Wenzel U. Amyloid-beta (Aβ1-42)-induced Paralysis in Caenorhabditis Elegans Is Reduced By Restricted Cholesterol Supply. Neurosci Lett. 2014 Jul 25;576:93-6. PubMed PMID: 24909620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced by restricted cholesterol supply. AU - Regitz,Charlotte, AU - Wenzel,Uwe, Y1 - 2014/06/05/ PY - 2014/01/28/received PY - 2014/05/05/revised PY - 2014/05/29/accepted PY - 2014/6/10/entrez PY - 2014/6/10/pubmed PY - 2015/1/6/medline KW - Alzheimer's disease KW - Amyloid β peptide KW - Caenorhabditis elegans KW - Cholesterol KW - Vitellogenin SP - 93 EP - 6 JF - Neuroscience letters JO - Neurosci Lett VL - 576 N2 - Alzheimer' disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). This process is influenced through supply of cholesterol via apolipoproteins to neurons. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, which expresses Aβ1-42 under control of a muscle-specific promoter, to test the effects of the apolipoprotein B homologue vitellogenin-6 on paralysis. Knockdown of vitellogenin-6 using RNA-interference (RNAi) recently was shown to significantly reduce cholesterol absorption in C. elegans, and both, RNAi for vitellogenin-6 or lowering the cholesterol concentration in the medium was associated with reduced Aβ-aggregation and paralysis in the nematodes. The effects of both interventions are mediated through the inhibition of the steroidal-signaling pathway since knockdown of its key factors DAF-9 or DAF-12 reduced paralysis independent of the cholesterol concentration and without additive effects by vitellogenin-6 RNAi. Double-RNAi for daf-12 and the downstream target of insulin-signaling, the foxo transcription factor daf-16, revealed that the paralysis-triggering effects of daf-16 RNAi were dominant over the preventive effects of daf-12 RNAi. Identical observations were made when the transcriptional co-activators of DAF-16, ftt-2 or par-5 were knocked down instead of daf-16. In conclusion, interactions between the steroidal and insulin-signaling pathways were identified in Aβ1-42 expressing CL2006, where cholesterol deprivation inhibits steroidal-signaling and thereby activates DAF-16-signaling. Those effects were associated with a reduced Alzheimer phenotype in the nematodes, i.e. reduced protein aggregation and paralysis. SN - 1872-7972 UR - https://www.unboundmedicine.com/medline/citation/24909620/Amyloid_beta__Aβ1_42__induced_paralysis_in_Caenorhabditis_elegans_is_reduced_by_restricted_cholesterol_supply_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(14)00459-5 DB - PRIME DP - Unbound Medicine ER -