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Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha.
Neurosci Lett. 2020 Jun 21; 730:135042.NL

Abstract

Alzheimer´s disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). Agonists of peroxisomal proliferator-activated receptors (PPARs) are discussed as anti-amyloidogenic compounds, e.g. due to their cholesterol-lowering activities. In a previous study we have shown in Caenorhabditis elegans expressing human Aβ in muscle cells, that inhibition of steroid-signaling, by RNAi of respective members of the signaling pathway or by reducing cellular cholesterol uptake, both increases the nuclear translocation of the foxo transcription factor DAF-16 and concomitantly reduces Aβ-induced paralysis. Using RNAi in the present study we show that NHR-49/PPARalpha inhibits steroidal-signaling upstream of DAF-9, a cytochrome P450-dependent enzyme which generates dafachronic acids as ligands for the nuclear hormone receptor DAF-12, and upstream of DAF-12 itself. The NHR-49/PPARalpha agonist fenofibrate reduces Aβ-induced paralysis in dependence on nhr-49 and nuclear translocation of DAF-16. In conclusion, activation of NHR-49/PPARalpha inhibits the steroidal-signaling pathway which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an Alzheimer model of C. elegans.

Authors+Show Affiliations

Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32413539

Citation

Leiteritz, Anne, et al. "Amyloid-beta (Aβ1-42)-induced Paralysis in Caenorhabditis Elegans Is Reduced Through NHR-49/PPARalpha." Neuroscience Letters, vol. 730, 2020, p. 135042.
Leiteritz A, Baumanns S, Wenzel U. Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha. Neurosci Lett. 2020;730:135042.
Leiteritz, A., Baumanns, S., & Wenzel, U. (2020). Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha. Neuroscience Letters, 730, 135042. https://doi.org/10.1016/j.neulet.2020.135042
Leiteritz A, Baumanns S, Wenzel U. Amyloid-beta (Aβ1-42)-induced Paralysis in Caenorhabditis Elegans Is Reduced Through NHR-49/PPARalpha. Neurosci Lett. 2020 Jun 21;730:135042. PubMed PMID: 32413539.
* 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 through NHR-49/PPARalpha. AU - Leiteritz,Anne, AU - Baumanns,Stefan, AU - Wenzel,Uwe, Y1 - 2020/05/12/ PY - 2020/02/12/received PY - 2020/05/07/accepted PY - 2020/5/16/pubmed PY - 2020/5/16/medline PY - 2020/5/16/entrez KW - Alzheimer’s disease KW - Amyloid β peptide KW - Caenorhabditiselegans KW - PPARalpha KW - Steroidal-signaling SP - 135042 EP - 135042 JF - Neuroscience letters JO - Neurosci. Lett. VL - 730 N2 - Alzheimer´s disease is a neurodegenerative disorder characterized by the misfolding and aggregation of amyloid β (Aβ). Agonists of peroxisomal proliferator-activated receptors (PPARs) are discussed as anti-amyloidogenic compounds, e.g. due to their cholesterol-lowering activities. In a previous study we have shown in Caenorhabditis elegans expressing human Aβ in muscle cells, that inhibition of steroid-signaling, by RNAi of respective members of the signaling pathway or by reducing cellular cholesterol uptake, both increases the nuclear translocation of the foxo transcription factor DAF-16 and concomitantly reduces Aβ-induced paralysis. Using RNAi in the present study we show that NHR-49/PPARalpha inhibits steroidal-signaling upstream of DAF-9, a cytochrome P450-dependent enzyme which generates dafachronic acids as ligands for the nuclear hormone receptor DAF-12, and upstream of DAF-12 itself. The NHR-49/PPARalpha agonist fenofibrate reduces Aβ-induced paralysis in dependence on nhr-49 and nuclear translocation of DAF-16. In conclusion, activation of NHR-49/PPARalpha inhibits the steroidal-signaling pathway which increases the nuclear translocation of DAF-16 and inhibits the Aβ-induced phenotype in an Alzheimer model of C. elegans. SN - 1872-7972 UR - https://www.unboundmedicine.com/medline/citation/32413539/Amyloid-beta_(Aβ1-42)-induced_paralysis_in_Caenorhabditis_elegans_is_reduced_through_NHR-49/PPARalpha L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(20)30312-8 DB - PRIME DP - Unbound Medicine ER -
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