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Amyloid-beta (Aβ1-42)-induced paralysis in Caenorhabditis elegans is reduced through NHR-49/PPARalpha.
Neuroscience Letters ( IF 2.5 ) Pub Date : 2020-05-12 , DOI: 10.1016/j.neulet.2020.135042
Anne Leiteritz 1 , Stefan Baumanns 1 , Uwe Wenzel 1
Affiliation  

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.

中文翻译:

通过线粒体NHR-49 / PPARalpha,可减少秀丽隐杆线虫的淀粉样β(Aβ1-42)诱导的麻痹。

阿尔茨海默氏病是一种神经退行性疾病,其特征在于淀粉样蛋白β(Aβ)的错误折叠和聚集。过氧化物酶体增殖物激活受体(PPAR)的激动剂被讨论为抗淀粉样蛋白的化合物,例如由于其降低胆固醇的活性。在先前的研究中,我们已经在秀丽隐杆线虫中在肌肉细胞中表达人Aβ的研究表明,通过信号传导途径各个成员的RNAi或通过减少细胞胆固醇的摄取来抑制类固醇信号传导,均会增加Foxo转录因子的核易位DAF-16并同时减轻Aβ引起的瘫痪。在本研究中使用RNAi,我们显示NHR-49 / PPARalpha抑制DAF-9上游的类固醇信号传导,一种细胞色素P450依赖性酶,它产生dafachronic酸作为核激素受体DAF-12的配体,并在DAF-12本身的上游。NHR-49 /PPARα激动剂非诺贝特可依赖nhr-49和DAF-16的核易位减少Aβ引起的瘫痪。总之,在秀丽隐杆线虫的阿尔茨海默病模型中,NHR-49 / PPARalpha的激活会抑制类固醇信号通路,从而增加DAF-16的核转运并抑制Aβ诱导的表型。
更新日期:2020-05-12
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